6481201	30	NAT2	*10	\N	Uncertain function	\N	\N	6481200	{17434923,18680467}	Inadequate	\N	NAT2*10 is assigned uncertain function based on inadequate evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*10 allele as "slow" and possibly substrate dependent. Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*10 is characterized by the core SNVs c.499G>A (p.E167K) and c.803G>A (p.R268K). c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. c.499G>A; p.E167K was shown to decrease N-acetylation activity toward sulfamethazine in vitro due to decreased protein levels (17434923). Published in silico modeling predicts that c.499G>A (p.E167K) decreases hydrogen bond capacity, decreases hydrophobicity, and alters protein charge (18680467). However, nine out of ten variant effect predictors tested by CPIC staff predict that c.499G>A is neutral/tolerated for protein function. The lack of in vivo evidence, along with the conflicting in vitro and computational evidence, results in the assignment of uncertain function.	\N	f
1406322	366	CYP2C9	*75	Unknown function	Unknown function	\N	n/a	1406321	{}	No evidence	\N	CYP2C9*75 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778063	380	CYP2D6	*65	\N	Uncertain function	\N	n/a	778062	{24647041,30366777}	Inadequate	\N	CYP2D6*65 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*65 demonstrated decreased enzyme activity compared to wildtype with various substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.029529046, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
778671	336	G6PD	Sinnai	III/Deficient	III/Deficient	\N	\N	778670	{22293322,10627140}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685851	175	RYR1	c.12413T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685850	{35849058}	\N	\N	PS4_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685943	175	RYR1	c.14558C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685942	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779477	362	TPMT	*41	\N	No function	\N	\N	779476	{28462921,32865889}	Limited	\N	TPMT*41 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*41 exhibited intermediate enzymatic activity (28462921, 32865889). In vitro studies using bacterial expression systems found that TPMT.41 exhibited decreased protein stability, decreased affinity for SAM, and decreased enzymatic activity compared to TPMT.1 (28462921, 32865889). Nine out of ten variant effect predictors tested by CPIC staff predict that the TPMT*41-defining SNV, c.719A>C (p.Y240S), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6481205	30	NAT2	*15	Slow	Decreased function	\N	\N	6481204	{28523442}	Moderate	\N	NAT2*15 is assigned decreased function based on moderate evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*15 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*15 is characterized by the core SNVs c.191G>A (p.R64Q, defining NAT2*14) and c.590G>A (p.R197Q, defining NAT2*6) and c.803G>A (p.R268K). c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. c.191G>A and c.590G>A have both repeatedly shown decreased NAT2 acetylation in numerous clinical and in vitro studies. An in vitro study using a bacterial expression system found that NAT2*15 exhibited significantly decreased N-acetyltransferase activity toward sulfamethazine and isoniazid and significantly decreased thermostability compared to the former reference NAT2*4 (28523442). Six and seven out of ten variant effect predictors tested by CPIC staff predict that c.191G>A (p.R64Q) and c.590G>A (p.R197Q) impair protein function, respectively. While c.191G>A and c.590G>A are both definitively attributed to decreased function individually, the combinatorial effects of having both variants present in the same allele are uncertain. Thus, NAT2*15 is assigned a moderate level of evidence.	\N	f
777803	366	CYP2C9	*68	Uncertain function	Uncertain function	\N	n/a	777802	{33536773}	Inadequate evidence	\N	CYP2C9*68 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variants present in CYP2C9*68 are predicted to be deleterious in SIFT and and benign in Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778067	380	CYP2D6	*69	\N	No function	\N	0.0	778066	{18797858}	Limited	\N	CYP2D6*69 is assigned no function based on limited evidence. CYP2D6*69 was identified in a subject demonstrating poor dextromethorphan metabolism (18797858). CYP2D6*69 is a rare allele defined by several SNPs including two which are attributed to the decreased function in other CYP2D6 alleles. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": 0.0, "European": 0.001, "Oceanian": null, "East Asian": 0.010007915, "Near Eastern": 0.0, "Central/South Asian": 0.002, "Sub-Saharan African": 0.001, "African American/Afro-Caribbean": 0.0}	f
777973	380	CYP2D6	*20	\N	No function	\N	0.0	777972	{10471072}	Limited	\N	CYP2D6*20 is assigned no function based on limited evidence. CYP2D6*20 was identified in a liver sample with decreased protein expression and decreased metoprolol metabolism (10471072). CYP2D6*20 is defined by a base insertion resulting in a frameshift and premature stop codon, yielding a truncated and nonfunctional enzyme. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": 0.0, "East Asian": 0.00011437685, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778450	365	DPYD	c.2194G>A (*6)	Normal function	Normal function	\N	1.0	778449	{23328581}	Moderate	\N	5-fluorouracil (in vitro)	{"Latino": 0.027319003, "European": 0.044963934, "East Asian": 0.018249057, "Central/South Asian": 0.09505568, "Sub-Saharan African": 0.02695635, "African American/Afro-Caribbean": 0.016}	f
778769	336	G6PD	Liuzhou	II/Deficient	II/Deficient	\N	\N	778768	{22293322,17018380}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685505	175	RYR1	c.5033A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685504	{35849058}	\N	\N	BP4	{"Latino": 0.0000654, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6481213	30	NAT2	*27	\N	Uncertain function	\N	\N	6481212	{19164093,29273096}	Inadequate	\N	NAT2*27 is assigned uncertain function based on inadequate evidence. NAT2*27 is characterized by the core SNVs c.589C>T and c.803G>A. c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. c.589C>T results in the amino acid change p.R197X, introducing a premature stop codon leading to the expression of a truncated protein product that is predicted to be nonfunctional (19164093, 29273096). Four out of four variant effect predictors tested by CPIC staff predict that c.589C>T (p.R197X) impairs function. While in silico predictions indicate that NAT2*27 exhibits decreased or possibly no enzymatic activity, the committee could not come to a consensus given the lack of in vitro or in vivo data to support the function.	\N	f
6481215	30	NAT2	*29	Slow	Decreased function	\N	\N	6481214	{10762005,28523442,15564878}	Moderate	\N	NAT2*29 is assigned decreased function based on moderate evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*29 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*29 is characterized by the functional SNVs c.191G>A (p.R64Q, defining NAT2*14) and c.341T>C (p.I114T, defining NAT2*5) which have both repeatedly shown decreased NAT2 N-acetylation in numerous in vivo and in vitro studies. A NAT2 phenotyping study showed that an individual genotyped as NAT2*14/*29 exhibited decreased acetylation of dapsone, with values below the cut-off value used to discriminate phenotypic rapid from slow acetylators (10762005). An in vitro study using a bacterial expression system found that NAT2*29 exhibits decreased thermostability and decreased N-acetyltransferase activity toward sulfamethazine and isoniazid (28523442 ). An additional in vitro study showed that NAT2*5 (which contains the core SNV c.341T>C, p.I114T) is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*29 would presumably be degraded in the same manner. Additionally, five and six out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) and c.191G>A (p.R64Q) impair protein function, respectively. While c.191G>A and c.341T>C are both definitively attributed to decreased function individually, the combinatorial effects of having both variants present in the same allele are uncertain.	\N	f
777963	380	CYP2D6	*14	\N	Decreased function	\N	0.5	777962	{18784265,19364831,24647041,30366777}	Limited	\N	CYP2D6*14 is assigned decreased function based on limited evidence. Three subjects with CYP2D6*1/*14, CYP2D6 *10/*14, and CYP2D6*14/*41 genotype, respectively demonstrated decreased dextromethorphan metabolism compared to wildtype based on urine metabolites (19364831). Multiple in vitro studies found CYP2D6*14 had modestly decreased enzyme activity compared to wildtype with various substrates (18784265, 19364831, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.0, "American": 0.0, "European": 0.0, "Oceanian": 0.0, "East Asian": 0.004713944, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778452	365	DPYD	c.2195T>G	Normal function	Normal function	\N	1.0	778451	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0019285714, "African American/Afro-Caribbean": 0.0}	f
6481217	30	NAT2	*30	Slow	Decreased function	\N	\N	6481216	{15558239,15564878}	Moderate	\N	NAT2*30 is assigned decreased function based on moderate evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*30 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*30 is characterized by the core SNVs: c.341T>C (p.I114T), 590G>A (p.R197Q), and c.803G>A (p.R268K). c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. c.341T>C (defining NAT2*5) and c.590G>A (defining NAT2*6) have both repeatedly shown decreased NAT2 N-acetylation in numerous in vivo and in vitro studies. NAT2*30 was reported in a clinical NAT2 phenotyping study using caffeine as a probe drug; 4 individuals heterozygous for NAT2*30 exhibited decreased acetylation of caffeine metabolites (15558239 ). An additional in vitro study showed that NAT2*5 (which contains the core SNV c.341T>C, p.I114T) is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*30 would presumably be degraded in the same manner. Five and seven out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) and c.590G>A (p.R197Q) impair protein function, respectively, while nine out of nine predictors tested by CPIC staff predict that c.803G>A (p.R268K) is neutral/tolerated for protein function. Though c.341T>C and:c.590G>A are both definitively attributed to decreased function individually, the combinatorial effects of having both variants present in the same allele are uncertain.	\N	f
778789	336	G6PD	Nankang	II/Deficient	II/Deficient	\N	\N	778788	{22293322,8807322,16329560}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.00014430014, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
3685749	175	RYR1	c.9499C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685748	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779415	362	TPMT	*10	\N	No function	\N	\N	779414	{13679074,10833476,16220112,18708949}	Limited	\N	TPMT*10 is assigned no function based on limited evidence. An individual genotyped TPMT*1/*10 was prescribed 50 mg/day 6-MP and experienced cytopenia after 3 months of treatment (10833476). In vitro studies found TPMT.10 protein expression is comparable to TPMT.1 in mammalian cells (16220112, 18708949) and yeast cells (13679074). TPMT.10 enzymatic activity is decreased by 30-70% in vitro relative to TPMT.1 (13679074, 16220112, 18708949) and TPMT.10 exhibited decreased affinity for 6-TG (18708949). Six out of ten variant effect predictors tested by CPIC staff predict that the TPMT*10-defining SNV, c.430G>C (p.G144R), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778883	336	G6PD	Nara	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778882	{22293322,8241497}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
6481221	30	NAT2	*32	Slow	Decreased function	\N	\N	6481220	{1559981,9173883,19909761,15564878}	Moderate	\N	NAT2*32 is assigned decreased function based on moderate evidence. NAT2*32 is characterized by the core SNVs c.203G>A (p.C68Y) and c.341T>C (p.I114T). An in vitro study showed that substituting a glycine in place of cysteine at position p.68 abolished NAT2 N-acetyltransferase activity toward sulfamethazine, procainamide, p-aminosalicylic acid, and 2-aminofluorene; the authors discuss the high probability that p.Cys68 lies within the NAT2 active site and is directly involved in acetyl transfer (1559981). An additional in vitro study found that NAT2 p.C68A exhibited undetectable N-acetyltransferase activity toward p-aminosalicylic acid and sulfamethazine (9173883). Thus, substitution of a tyrosine in place of cysteine at residue p.68 would likely abolish NAT2 enzymatic activity. Published in silico modeling predicts that c.203G>A (p.C68Y) alters the NAT2 catalytic mechanism, rendering the protein non-functional (19909761). Lastly, nine out of ten variant effect predictors tested by CPIC staff predict that c.203G>A (p.C68Y) impairs protein function. c.341T>C (p.I114T) defines NAT2*5, which has repeatedly shown decreased NAT2 acetylation activity in numerous in vivo and in vitro studies. Additionally, an in vitro study showed that NAT2*5 is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*32 would presumably be degraded in the same manner. While the committee agreed to the assignment of decreased function based on the function of c.341T>C (p.I114T), there was a lack of consensus regarding the function of c.203G>A (p.C68Y). It remains unknown whether there are any combinatorial effects associated with c.341T>C and c.203G>A.	\N	f
6481225	30	NAT2	*34	Slow	Decreased function	\N	\N	6481224	{28523442,9154882,15558239,17011540,28959610}	Definitive	\N	NAT2*34 is assigned decreased function based on definitive evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*34 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*34 is characterized by the core SNV c.590G>A (p.R197Q) which has been studied for more than 25 years and has shown decreased NAT2 N-acetylation activity in numerous in vivo and in vitro studies using various substrates. In vivo phenotyping studies have demonstrated that individuals heterozygous for NAT2*34 in combination with another decreased function allele exhibit decreased N-acetylation activity toward caffeine metabolites (15558239, 17011540) and isoniazid (9154882, 28959610). Seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. In vitro studies have shown that NAT2*34 exhibits decreased thermostability and decreased N-acetyltransferase activity toward sulfamethazine and isoniazid (28523442).	\N	f
777797	366	CYP2C9	*65	Uncertain function	Uncertain function	\N	n/a	777796	{33536773}	Inadequate evidence	\N	CYP2C9*65 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variant present in CYP2C9*65 is predicted to be deleterious in both SIFT and Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777451	384	CYP2B6	*15	Decreased or no function	Uncertain function	\N	\N	777450	{15190123,17559344,20517174,20662624,21746968,30201214}	Limited	\N	CYP2B6*15 (c.1172T>A, p.I391N) – Uncertain function: CYP2B6*15 is assigned uncertain function. In vitro studies using human liver microsomes (17559344, 15190123) and cDNA expression systems (15190123, 20517174, 21746968, 30201214) showed decreased to no enzyme activity for CYP2B6*15 compared to the *1 reference (20662624). However, due to the lack of any in vivo or clinical evidence, consensus among experts was uncertain function based on limited evidence.	{"Latino": 0.0016141976, "European": 0.0069231493, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.00009347988, "Sub-Saharan African": 0.014535101, "African American/Afro-Caribbean": 0.0}	f
777569	384	CYP2C19	*19	\N	Decreased function	\N	\N	777568	{17455109,18312490,21325430,25001882,21692664}	Limited	\N	CYP2C19*19 is assigned decreased function based on limited evidence. In vitro studies found CYP2C19*19 had decreased intrinsic clearance compared to wildtype with mephenytoin, omeprazole, and clopidogrel substrates (17455109, 21325430, 25001882). Although two in vitro studies found CYP2C19*19 demonstrated similar intrinsic clearance compared to wildtype with omeprazole and mephenytoin, the experts did not find these results convincing as CYP2C19*19 also demonstrated higher Km values compared to wildtype in these studies, suggesting CYP2C19*19 has decreased substrate affinity (18312490, 21325430). Additionally, decreased intrinsic clearance compared to wildtype with these two substrates was previously reported as mentioned above. Another study found CYP2C19*19 exhibited significantly reduced catalytic activities compared with CYP2C19*1 across multiple substrates (21692664).Therefore, consensus among experts was decreased function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00019673406, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779003	336	G6PD	Andalus	II/Deficient	II/Deficient	\N	\N	779002	{22293322,12497642,32425388,16088936,2393028}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.00007233273, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778815	336	G6PD	Minnesota, Marion, Gastonia, LeJeune	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778814	{22293322,1999409,1805484}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.00001025599, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
3685423	175	RYR1	c.1475G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685422	{35849058}	\N	\N	PM1	{"Latino": null, "American": null, "European": 0.00008823, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0001208}	f
3685797	175	RYR1	c.11126C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685796	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777735	384	CYP2C9	*34	Uncertain function	Uncertain function	\N	n/a	777734	{23752738,18971529,19541829,23844998,24118918,25142737,25144335,25951663,25476996,25614704,25832633,25884291,25924705,27163851,24077631}	Inadequate evidence	\N	CYP2C9*34 is assigned uncertain function due to inadequate evidence. Although one subject with CYP2C9*1/*34 genotype exhibited decreased clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704), in vitro studies found CYP2C9*34 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (23752738, 18971529, 23844998, 19541829, 24118918, 25142737, 25476996, 25614704, 25832633, 25884291, 25924705, 27163851, 24077631, 25144335, 25951663). Consensus was not achieved among experts and therefore uncertain function was assigned..	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0002119417, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778055	380	CYP2D6	*61	\N	Uncertain function	\N	n/a	778054	{24647041,30366777}	Inadequate	\N	CYP2D6*61 is assigned uncertain function due to inadequate evidence. In vitro studies have found CYP2D6*61 demonstrated decreased to no detectable enzyme activity compared to wildtype with various substrates (24647041, 30366777) but consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685495	175	RYR1	c.4711A>G	Likely Benign	Normal function	\N	n/a	3685494	{33767344}	\N	\N	BS1	{"Latino": 0.002684, "American": null, "European": 0.001618, "East Asian": null, "Near Eastern": 0.001441, "Central/South Asian": 0.0008278, "Sub-Saharan African": 0.00009656}	f
3685845	175	RYR1	c.12383C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685844	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685873	175	RYR1	c.13513G>C	Benign	Normal function	\N	n/a	3685872	{33767344}	\N	\N	BA1	{"Latino": 0.0019, "American": null, "European": 0.0050225807, "East Asian": null, "Near Eastern": 0.004899, "Central/South Asian": 0.00207, "Sub-Saharan African": 0.001231}	f
3685897	175	RYR1	c.14126C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685896	{33767344}	\N	\N	PM1_Sup, PP3_Mod, BS3_Sup	{"Latino": null, "American": null, "European": null, "East Asian": 0.0001928, "Near Eastern": 0.001442, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685901	175	RYR1	c.14186A>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685900	{35849058}	\N	\N	PM1_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685921	175	RYR1	c.14458G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685920	{35849058}	\N	\N	PS4_Sup, PM1_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6355280	33	CFTR	G1249R(G>A)	\N	ivacaftor responsive	\N	\N	6355279	{}	\N	\N	\N	\N	f
6355282	33	CFTR	G1249R(G>C)	\N	ivacaftor responsive	\N	\N	6355281	{}	\N	\N	\N	\N	f
6355288	33	CFTR	H1375P	\N	ivacaftor responsive	\N	\N	6355287	{}	\N	\N	\N	\N	f
6355286	33	CFTR	H939R	\N	ivacaftor responsive	\N	\N	6355285	{}	\N	\N	\N	\N	f
6355290	33	CFTR	I148T	\N	ivacaftor responsive	\N	\N	6355289	{}	\N	\N	\N	\N	f
6355292	33	CFTR	I175V	\N	ivacaftor responsive	\N	\N	6355291	{}	\N	\N	\N	\N	f
6355294	33	CFTR	I807M	\N	ivacaftor responsive	\N	\N	6355293	{}	\N	\N	\N	\N	f
6355404	33	CFTR	V1293G	\N	ivacaftor responsive	\N	\N	6355403	{}	\N	\N	\N	\N	f
6355406	33	CFTR	W1282R	\N	ivacaftor responsive	\N	\N	6355405	{}	\N	\N	\N	\N	f
6355408	33	CFTR	Y1014C	\N	ivacaftor responsive	\N	\N	6355407	{}	\N	\N	\N	\N	f
6355410	33	CFTR	Y1032C	\N	ivacaftor responsive	\N	\N	6355409	{}	\N	\N	\N	\N	f
6481227	30	NAT2	*35	Slow	Decreased function	\N	\N	6481226	{19909761}	Moderate	\N	NAT2*35 is assigned decreased function based on moderate evidence. NAT2*35 is characterized by the core SNVs c.152G>T (p.G51V), c.590G>A (p.R197Q, defining NAT2*6), and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. Published in silico modeling predicts that c.152G>T (p.G51V) alters substrate binding (19909761). Four out of ten variant effect predictors tested by CPIC staff predict that c.152G>T (p.G51V) impairs NAT2 protein function. c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. Thus, NAT2*35 is assigned decreased function based on c.590G>A (p.R197Q). Despite this, it remains unknown whether there are any combinatorial effects associated with c.152G>T and c.590G>A.	\N	f
779089	142	NUDT15	*13	\N	No function	\N	\N	779088	{29519865}	Limited	\N	NUDT15*13 is assigned no function based on limited evidence. The NUDT15*13 SNV (NM_018283.4:c.343dup) results in a frameshift at amino acid residue 115 and the loss of the enzymatic domain (29519865). Patients carrying a NUDT15*13 allele had a 33% reduction in thiopurine dosage following the occurrence of adverse reactions (29519865). NUDT15*13 is characterized by the duplication c.343_344insG (p.E115fs), which is predicted to impair protein function by CADD and Phd-SNPg	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
3685361	175	RYR1	c.529C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685360	{35849058}	\N	\N	PS2_PM6_Mod, PS4, PM1, PP1_St, PP3_Mod, BS2_Mod	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
7219573	14	NAT2	*71	\N	Unknown function	\N	\N	7219572	{}	No evidence	\N	NAT2*71 is assigned unknown function based on a lack of evidence. NAT2*71 is defined by c.704T>G (p.V235G) for which there is no literature describing function. Seven out of ten variant effect predictors tested by CPIC staff predict that c.704T>G (p.V235G) impairs protein function.	\N	f
7219579	14	NAT2	*74	\N	Unknown function	\N	\N	7219578	{}	No evidence	\N	NAT2*74 is assigned unknown function based on a lack of evidence. NAT2*74 is defined by the core SNVs c.803G>A (p.R268K) and c.845A>G (p.K282R). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.845A>G (p.K282R). Three out of ten variant effect predictors tested by CPIC staff predict that c.845A>G (p.K282R) impairs protein function.	\N	f
777555	384	CYP2C19	*12	\N	Uncertain function	\N	\N	777554	{12464799}	Inadequate	\N	CYP2C19*12 is assigned uncertain function due to inadequate evidence. In one in vitro study CYP2C19*12 was poorly expressed and enzyme activity could not be assessed with a mephenytoin substrate (12464799). CYP2C19*12 is defined by the conversion of the stop codon to cysteine, and it is unclear if this protein is unstable in vivo. Therefore, consensus among experts was not achieved and uncertain function was assigned.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.000108813925, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0011203007}	f
6235908	35	CYP4F2	*19	\N	\N	\N	\N	6235907	\N	\N	\N	\N	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6355368	33	CFTR	R1162L	\N	ivacaftor responsive	\N	\N	6355367	{}	\N	\N	\N	\N	f
6355370	33	CFTR	R1283M	\N	ivacaftor responsive	\N	\N	6355369	{}	\N	\N	\N	\N	f
6355356	33	CFTR	R553Q	\N	ivacaftor responsive	\N	\N	6355355	{}	\N	\N	\N	\N	f
6355358	33	CFTR	R668C	\N	ivacaftor responsive	\N	\N	6355357	{}	\N	\N	\N	\N	f
6355360	33	CFTR	R792G	\N	ivacaftor responsive	\N	\N	6355359	{}	\N	\N	\N	\N	f
6355362	33	CFTR	R933G	\N	ivacaftor responsive	\N	\N	6355361	{}	\N	\N	\N	\N	f
6355386	33	CFTR	S1159F	\N	ivacaftor responsive	\N	\N	6355385	{}	\N	\N	\N	\N	f
6355388	33	CFTR	S1159P	\N	ivacaftor responsive	\N	\N	6355387	{}	\N	\N	\N	\N	f
6355378	33	CFTR	S589N	\N	ivacaftor responsive	\N	\N	6355377	{}	\N	\N	\N	\N	f
6355380	33	CFTR	S737F	\N	ivacaftor responsive	\N	\N	6355379	{}	\N	\N	\N	\N	f
3685821	175	RYR1	c.11947C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685820	{33767344}	\N	\N	PS2_PM6_Mod, PS4_Sup, PP3_Mod, BS3_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777425	384	CYP2B6	*2	Normal function	Normal function	\N	\N	777424	{12642465,17559344,21896912,22471906,23254426,23399569,26655325,30201214}	Strong	\N	CYP2B6*2 (c.64C>T, p.R22C) - Normal function: CYP2B6*2 is assigned normal function based on in vivo (heterozygous patients) and in vitro studies. Multiple studies evaluating efavirenz plasma concentrations among patients with HIV found that CYP2B6*2 heterozygotes had similar efavirenz plasma concentrations compared to the *1 reference (21896912, 22471906, 23254426, 23399569). A study evaluating efavirenz content in hair samples among HIV patients taking efavirenz for more than three months, similarly found that CYP2B6*2 did not impact long term efavirenz exposure (26655325). Additionally, one in vitro study using human liver microsomes (17559344) and two in vitro studies using cDNA expression systems (12642465, 30201214) found that CYP2B6*2 had similar enzyme activity compared to the *1 reference. Therefore, consensus among experts was normal function based on strong evidence.	{"Latino": 0.044, "European": 0.04917699, "Oceanian": 0.0, "East Asian": 0.045823272, "Near Eastern": 0.039, "Central/South Asian": 0.041, "Sub-Saharan African": 0.031, "African American/Afro-Caribbean": 0.031030929}	f
3685447	175	RYR1	c.1834G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685446	{35849058}	\N	\N	PS4_Sup, PP1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685689	175	RYR1	c.7528T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685688	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685923	175	RYR1	c.14458G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685922	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685967	175	RYR1	c.14814C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685966	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685977	175	RYR1	c.14918C>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685976	{33767344}	\N	\N	PS4_Mod, PM1_Sup, PP3_Mod, PP1_Sup	{"Latino": null, "American": null, "European": 0.0000441, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002414}	f
3685727	175	RYR1	c.8518C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685726	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": 0.00001471, "East Asian": 0.0001936, "Near Eastern": null, "Central/South Asian": 0.0002082, "Sub-Saharan African": null}	f
3685739	175	RYR1	c.8926C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685738	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685751	175	RYR1	c.9635A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685750	{35849058}	\N	\N	None	{"Latino": 0.00006544, "American": null, "European": 0.00059750484, "East Asian": null, "Near Eastern": 0.0002884, "Central/South Asian": null, "Sub-Saharan African": 0.00009651}	f
3685765	175	RYR1	c.9850T>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685764	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685817	175	RYR1	c.11798A>G	Likely Benign	Normal function	\N	n/a	3685816	{33767344}	\N	\N	PP3_Mod, BS1	{"Latino": 0.002551, "American": null, "European": 0.001647, "East Asian": null, "Near Eastern": 0.001441, "Central/South Asian": 0.0008288, "Sub-Saharan African": 0.0000966}	f
3685819	175	RYR1	c.11813G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685818	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779023	336	G6PD	Kaiping, Anant, Dhon, Sapporo-like, Wosera	II/Deficient	II/Deficient	\N	\N	779022	{22293322,8935319,1953767}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0070355837, "Central/South Asian": 0.000052762094, "African American/Afro-Caribbean": 0.0}	f
3685893	175	RYR1	c.14002C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685892	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": 0.00009414, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779308	362	SLCO1B1	*16	\N	Uncertain function	\N	\N	779307	{12811365,33658230}	Inadequate	\N	SLCO1B1*16 is assigned uncertain function based on limited in vitro evidence and clinical data. One clinical study showed 2 heterozygous subjects treated with pravastatin had similar pharmacokinetic parameters to subjects with wildtype alleles and one invitro study found normal protein expression (33658230). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": 0.0005718263, "Oceanian": null, "East Asian": 0.0045032115, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779342	362	SLCO1B1	*33	\N	Uncertain function	\N	\N	779341	{22147369,33658230}	Inadequate	\N	SLCO1B1*33 is assigned uncertain function based on limited in vitro evidence and clinical data. One clinical study showed no statistical difference in methotrexate clearance (22147369) and one in vitro study found decreased protein expression (33658230). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777745	384	CYP2C9	*39	No function	No function	\N	0.0	777744	{24077631,24118918,25142737,25144335,25476996,25832633,25951663,25884291,27163851,23844998}	Limited	\N	CYP2C9*39 is assigned no function based on limited evidence. Multiple in vitro studies found CYP2C9*39 demonstrated decreased clearance with numerous substrates compared to wildtype (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25951663, 25884291, 27163851, 23844998). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function or decreased function alleles.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3318600	133	CYP4F2	*15	\N	\N	\N	\N	3318599	\N	\N	\N	\N	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778837	336	G6PD	Aveiro	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778836	{22293322,10666231}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779435	362	TPMT	*20	\N	No function	\N	\N	779434	{18708949,16917910}	Limited	\N	TPMT*20 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*20 exhibited intermediate activity and this patient experienced azathioprine-related pancreatitis (16917910). An in vitro study using a mammalian cell expression system found that TPMT.20 exhibited decreased affinity for 6-TG and enzymatic activity was reduced by 75% compared to TPMT.1 (18708949). Two out of ten variant effect predictors tested by CPIC staff predict that the TPMT*20-defining SNV, c.712A>G (p.K238E), impairs protein function.	{"Latino": 0.0, "European": 0.00005133778, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777575	384	CYP2C19	*24	\N	No function	\N	\N	777574	{25001882,27578295,31713493}	Limited	\N	CYP2C19*24 is assigned no function based on limited evidence. In vitro studies found CYP2C19*24 demonstrated nondetectable enzyme activity compared to wildtype with mephenytoin, clopidogrel, and omeprazole substrates (25001882, 27578295, 31713493). Additionally, CYP2C19*24 had less holoprotein compared to wildtype suggesting the protein is less stable resulting in little to no enzyme activity (27578295). Therefore, consensus among experts was no function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function and decreased function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00018712576, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777799	366	CYP2C9	*66	Uncertain function	Uncertain function	\N	n/a	777798	{33536773}	Inadequate evidence	\N	CYP2C9*66 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variant present in CYP2C9*66 is predicted to be tolerated in SIFT and benign in Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.00080, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1777311	288	CYP2D6	*4x2	\N	No function	\N	0.0	777942	{10022755,12152006}	Moderate	\N	CYP2D6*4x2 is assigned no function based on moderate evidence. CYP2D6*4x2 has been described in subjects demonstrating decreased metabolism of dextromethorphan or debrisoquine (10022755, 12152006). CYP2D6*4 is defined by a splicing defect resulting in a nonfunctional protein and gene duplication would therefore not impact enzyme activity. Therefore, consensus among experts was no function with an activity value of 0 based on moderate evidence.	{"Latino": 0.0040316023, "American": 0.0010676404, "European": 0.0065507535, "Oceanian": 0.0, "East Asian": 0.0, "Near Eastern": 0.0032411083, "Central/South Asian": 0.00047151276, "Sub-Saharan African": 0.019609926, "African American/Afro-Caribbean": 0.026700884}	f
3685667	175	RYR1	c.7358T>C	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685666	{35849058}	\N	\N	PS2_PM6_Mod, PS4_Sup, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685695	175	RYR1	c.7771C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685694	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685905	175	RYR1	c.14201G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685904	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685919	175	RYR1	c.14449A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685918	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779475	362	TPMT	*40	\N	Uncertain function	\N	\N	779474	{27564568,29785012}	Inadequate	\N	TPMT*40 is assigned uncertain function based on inadequate evidence. Erythrocytes from an individual genotyped TPMT*1/*40 exhibited intermediate enzymatic activity, however there was no difference in thiopurine dose intensity between TPMT*1/*1 patients and one patient genotyped TPMT*1/*40 (27564568). TPMT.40 exhibited comparable protein expression to TPMT.1 in mammalian cells (29785012). Three out of ten variant effect predictors tested by CPIC staff predict that the TPMT*40-defining SNV, c.677G>A (p.R226Q), impairs protein function.	{"Latino": 0.0002034, "European": 0.00005903421, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779431	362	TPMT	*18	\N	No function	\N	\N	779430	{18708949,15226673}	Limited	\N	TPMT*18 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*18 exhibited intermediate activity (15226673). An in vitro study using a mammalian cell expression system found that TPMT.18 protein expression is decreased compared to TPMT.1 and TPMT.18 enzymatic activity is undetectable (18708949). Ten out of ten variant effect predictors tested by CPIC staff predict that the TPMT*18-defining SNV, c.211G>A (p.G71R) impairs protein function.	{"Latino": 0.0, "European": 0.000011514104, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777689	384	CYP2C9	*11	Decreased function	Decreased function	\N	0.5	777688	{15284535,23752738,15289788,15970795,25951663,16220110,21811894,23844998,24118918,25142737,25144335,25476996,25832633,25884291,25924705,27163851,27199745,24077631}	Definitive	\N	CYP2C9*11 is assigned decreased function based on definitive evidence in heterozygous patients and in vitro studies. Four subjects carrying the CYP2C9*11 allele (n=3 CYP2C9*1/*11, n=1 CYP2C9*8/*11) demonstrated decreased phenytoin metabolism compared to wildtype subjects based on urinary excretion of a phenytoin metabolite after a single 300mg dose (16220110). Three CYP2C9*1/*11 patients on a stable dose of warfarin required a 33% lower warfarin dose compared to CYP2C9*1/*1 patients which correlated with the in vitro investigation where CYP2C9*11 had low levels of enzyme expression, decreased half-life, and 70% catalytic efficiency compared to wildtype; these results are suggestive of improper protein folding leading to decreased stability and reduced enzyme activity (15970795). An examination of the crystal structure showed the substitution which defines the CYP2C9*11 allele disrupts the sole extrahelical hydrogen bonding interaction, destabilizing the structure (15284535). In vitro studies showed CYP2C9*11 demonstrated decreased metabolism of tolbutamide, warfarin, glimepiride, carvedilol, fluoxetine, flurbiprofen, mestranol, diclofenac, and losartan compared to wildtype (15284535, 23752738, 24118918, 25476996, 25884291, 27199745, 25144335, 25924705, 25951663, 23844998). Although other in vitro studies showed CYP2C9*11 had similar activity compared to wildtype, the experts did not find these results convincing as in these studies CYP2C9*2 and/or CYP2C9*3 which definitively have decreased function and no function, respectively, also demonstrated similar activity compared to wildtype in these studies (25142737, 25832633, 27163851). The experts did not find the result of an in vitro study which showed CYP2C9*11 had similar activity compared to wildtype with a tolbutamide substrate (24077631) convincing because this result was not replicated as two separate in vitro studies which used two different systems and showed CYP2C9*11 demonstrated decreased clearance compared to wildtype, as described previously (15284535, 23752738). The experts also did not deem the results of a study which found no difference in losartan metabolism among four subjects carrying the CYP2C9*11 allele nor a study which found no difference in acenocoumarol metabolism among one subject with CYP2C9*1/*11 genotype as convincing conflicting evidence due to the small sample size (15289788, 21811894). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on definitive evidence.	{"Latino": 0.002901849, "American": 0.0028040742, "European": 0.0016443896, "Oceanian": null, "East Asian": 0.00029316536, "Near Eastern": 0.0, "Central/South Asian": 0.0010429447, "Sub-Saharan African": 0.025685642, "African American/Afro-Caribbean": 0.013860963}	f
777703	384	CYP2C9	*18	Uncertain function	Uncertain function	\N	n/a	777702	{23752738,16099926}	Inadequate evidence	\N	CYP2C9*18 is assigned uncertain function due to inadequate evidence. In one in vitro study, CYP2C9*18 protein expression could not be detected in an E.coli system (16099926). CYP2C9*18 protein expression was detected in a separate study using COS-7 cells and no enzyme activity was detected with warfarin and tolbutamide substrates (23752738). Therefore, consensus among experts was uncertain function due to insufficient evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779445	362	TPMT	*25	\N	No function	\N	\N	779444	{18602085}	Moderate	\N	TPMT*25 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*1/*25 exhibited intermediate enzymatic activity (18602085). An in vitro study using a yeast expression system found that TPMT.25 exhibited decreased affinity for 6-TG and TPMT.25 enzymatic activity is decreased by 30% compared to TPMT.1 (18602085). Seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*25-defining SNV, c.634T>C (p.C212R), impairs protein function.	{"Latino": null, "European": 0.00010, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778973	336	G6PD	Kawasaki	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778972	{22293322,1945893}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685677	175	RYR1	c.7373G>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685676	{35849058}	\N	\N	PS4_Mod, PM1_Sup, PM5, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778061	380	CYP2D6	*64	\N	Uncertain function	\N	n/a	778060	{24647041,30366777}	Inadequate	\N	CYP2D6*64 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*64 demonstrated decreased enzyme activity compared to wildtype with various substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
779223	363	RYR1	c.7522C>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	779222	{33767344}	\N	\N	PS3_St, PS4_Mod, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
1357092	345	SLCO1B1	*48	\N	No function	\N	\N	1357091	{22232210}	Limited	\N	SLCO1B1*48 is assigned no function due to evidence supporting a full gene deletion (22232210). Therefore, consensus among experts was no function due to limited evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779425	362	TPMT	*15	\N	No function	\N	\N	779424	{15083071,31005613}	Limited	\N	TPMT*15 is assigned no function based on limited evidence. Erythrocytes from a patient genotyped TPMT*3A/*15 exhibited very low enzymatic activity (15083071, 31005613). The patient's mother was genotyped TPMT*1/*15 and exhibited intermediate enzymatic activity (15083071). The TPMT*15-defining SNV, c.495-1G>A, disrupts the canonical splice site and results in the loss of exon 7, which is further supported by SpliceAI predictions. Additionally, the variant effect predictors, CADD and PhD-SNPg, predict that c.495-1G>A impairs protein function.	{"Latino": 0.0, "European": 0.000045666697, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779443	362	TPMT	*24	\N	Uncertain function	\N	\N	779442	{18602085,27564568,29785012,33118454,34412101}	Inadequate	\N	TPMT*24 is assigned uncertain function based on inadequate evidence. Erythrocytes from individuals genotyped TPMT*1/*24 exhibited intermediate activity (18602085, 27564568), while erythrocytes from individuals genotyped TPMT*3A/*24 or *3C/*24 exhibited low enzymatic activity (33118454). There is no difference in thiopurine dose intensity observed between individuals genotyped TPMT*1/*1 and TPMT*1/*24 (27564568, 34412101). An in vitro study using a yeast expression system found that TPMT.24 exhibited decreased affinity for 6-TG, but the rate of enzymatic activity is unaffected compared to TPMT.1 (18602085). TPMT.24 exhibited comparable protein expression to TPMT.1 in mammalian cells (29785012). One out of ten variant effect predictors tested by CPIC staff predicts that the TPMT*24-defining SNV, c.537G>T (p.Q179H), impairs protein function.	{"Latino": 0.001137, "European": 0.000026354577, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0328}	f
777987	380	CYP2D6	*27	\N	Normal function	\N	1.0	777986	{18784265,18838503,24647041,30366777}	Limited	\N	CYP2D6*27 is assigned normal function based on limited evidence. Multiple in vitro studies found CYP2D6*27 demonstrated similar activity compared to wildtype with various substrates (18784265, 18838503). Although some in vitro studies found CYP2D6*27 demonstrated modestly decreased activity it was not convincing the magnitude of decreased activity was clinically significant (24647041, 30366777). Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence as it was determined the phenotypes containing this allele would be clinically similar to phenotypes comprising normal function alleles.	{"Latino": null, "American": 0.003, "European": 0.0, "Oceanian": null, "East Asian": 0.00056961953, "Near Eastern": 0.007, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0033542388, "African American/Afro-Caribbean": 0.003}	f
779483	142	TPMT	*44	\N	No function	\N	\N	779482	{31005613,32865889}	Moderate	\N	TPMT*44 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*1/*44 exhibited intermediate enzymatic activity (31005613, 32865889). Recombinant TPMT.44 expressed in E coli. exhibited decreased protein stability (31005613) and protein abundance was low when expressed in mammalian cells (29785012). Ten out of ten variant effect predictors tested by CPIC staff predict that the TPMT*44-defining SNV, c.497A>G (p.Y166C), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778492	365	DPYD	c.3067C>A	Normal function	Normal function	\N	1.0	778491	{23588312}	Limited	\N	5-fluorouracil (ex vivo)	{"Latino": 0.00089275226, "European": 0.000013283348, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.034825396, "African American/Afro-Caribbean": 0.044617835}	f
7726083	2	TPMT	*45	\N	No function	\N	\N	7726082	{33273844,34412101,29785012}	Limited	\N	TPMT*45 is assigned no function based on limited evidence. A patient genotyped TPMT*1/*45 exhibited low TPMT enzymatic activity and a plasma 6-TGN concentration above the therapeutic range (33273844). Following reduction of the thiopurine dosage, the patient's 6-TGN plasma concentration decreased and was within the therapeutic range (33273844). However, another patient genotyped TPMT*1/*45 tolerated a 6-MP dose of 73.1 mg/m2 (34412101). TPMT*45 results in the generation of a premature stop codon at residue 226 and the production of a truncated protein. The premature stop occurs upstream of the known "no function" variant (c.719A>G, defining TPMT*3C), suggesting that loss of this region of the protein alters function. Two out of four variant effect predictors tested by CPIC staff predict that the TPMT*45-defining SNV, c.676C>T (p.R226X), impairs protein function. In a study of variant abundance by massively parallel sequencing, the TPMT*45 variant was found to have low protein abundance (29785012).	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778957	336	G6PD	Anadia	II/Deficient	II/Deficient	\N	\N	778956	{22293322,1945893,18056001}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685711	175	RYR1	c.8026C>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685710	{35849058}	\N	\N	PS4_Mod, PP1_St	{"Latino": null, "American": null, "European": 0.0000294, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685761	175	RYR1	c.9797T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685760	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685771	175	RYR1	c.10043G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685770	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777263	236	CACNA1S	Reference	\N	Normal function	\N	\N	777262	{}	\N	\N	\N	\N	f
5409120	38	CYP2D6	*176	\N	\N	\N	\N	5409119	\N	\N	\N	\N	\N	f
778961	336	G6PD	Clinic	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778960	{22293322,7825590}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778881	336	G6PD	Kalyan-Kerala, Jamnaga, Rohini	III/Deficient	III/Deficient	\N	\N	778880	{22293322,1303182,15996881}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.00004499883, "East Asian": 0.0, "Central/South Asian": 0.011377339, "African American/Afro-Caribbean": 0.0}	f
778697	336	G6PD	Metaponto	III/Deficient	III/Deficient	\N	\N	778696	{22293322,2253938}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
7726085	2	TPMT	*46	\N	No function	\N	\N	7726084	{35931342}	Limited	\N	TPMT*46 is assigned no function based on limited evidence. TPMT*46 is characterized by two SNVs: c.487C>T, p.R163C (the *33 variant) and c.644G>A, p.R215H (the *8 variant). TPMT*8 is assigned decreased function and TPMT*33 is assigned no function. Nine out of ten variant effect predictors tested by CPIC staff predict that c.644G>A (p.R215H) is neutral for protein function and seven out of ten predict that c.487C>T (p.R163C) impairs protein function. TPMT*46 is assigned no function based on the *33 SNV (c.487C>T; p.R163C).	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
7726087	2	TPMT	*47	\N	No function	\N	\N	7726086	{}	Limited	\N	TPMT*47 is assigned no function based on limited evidence. TPMT*47 is characterized by a four base pair deletion in exon II (c.21_24delACTT) resulting in a frameshift of the coding sequence and the creation of a premature stop codon, which is predicted to undergo nonsense-mediated decay. The variant effect predictors, CADD and PhD-SNPg, predict that c.21_24del impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778025	380	CYP2D6	*46	\N	Normal function	\N	1.0	778024	{15768052,24647041,30366777}	Limited	\N	CYP2D6*46 is assigned normal function based on limited evidence. Subjects carrying the CYP2D6*46 allele demonstrated similar dextromethorphan metabolism and tramadol pharmacokinetics compared to subjects with two functional alleles (15768052). An vitro study found CYP2D6*46 demonstrated similar activity compared to wildtype with dextromethorphan and bufuralol substrates (15768052). Although two in vitro study found CYP2D6*46 demonstrated decreased enzyme activity compared to wildtype with dextromethorphan, bufuralol, and primaquine substrates (24647041, 30366777) the experts did not find this result convincing as CYP2D6*46 demonstrated similar activity compared to wildtype in vivo and in vitro with the same substrates. Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence.	{"Latino": null, "American": 0.001, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.003, "Central/South Asian": 0.0, "Sub-Saharan African": 0.004215873, "African American/Afro-Caribbean": 0.010738235}	f
778099	380	CYP2D6	*90	\N	Uncertain function	\N	n/a	778098	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*90 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*90 demonstrated enzyme activity ranging from increased to decreased activity compared to wildtype with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). Therefore, consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685841	175	RYR1	c.12310G>C	Likely Benign	Normal function	\N	n/a	3685840	{35849058}	\N	\N	BS2_Mod, BP4	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685915	175	RYR1	c.14422_14423delinsAA	Variant of uncertain significance	Uncertain function	\N	n/a	3685914	{35849058}	\N	\N	PM1_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
1002702	356	SLCO1B1	*45	\N	No function	\N	\N	1002701	{38674010,32082363,36964102,39071607,25546334,40199401,37674011}	Moderate	\N	SLCO1B1*45 is assigned no function based on moderate evidence. SLCO1B1*45 is defined by c.1738C>T (p.R580X). This variant generates a premature stop codon resulting in the expression of a truncated protein. SLCO1B1*45 was significantly associated with increased bilirubin levels and an individual carrying SLCO1B1*45 experienced statin-associated muscle symptoms (38674010). Additionally, SLCO1B1 loss-of-function has been implicated in the pathogenesis of Rotor syndrome and SLCO1B1*45 has been identified in a homozygous state in probands (32082363, 36964102, 39071607, 25546334). Cryo-EM structural studies of SLCO1B1 protein have consistently identified p.R580 as a critical amino acid involved in substrate recognition and binding (40199401, 37674011). The SLCO1B1 protein contains 12 transmembrane domains; a truncation at p.R580 eliminates the final two transmembrane domains which is highly disruptive rendering the protein non-functional, as the full transmembrane architecture is required for substrate transport. Four out of four VEPs capable of making predictions for nonsense variants predict that c.1738C>T impairs protein function.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777310	234	CFTR	2789+5G->A	\N	ivacaftor responsive	\N	\N	777309	{}	\N	ACMG screening panel	\N	\N	f
777587	384	CYP2C19	*31	\N	Uncertain function	\N	\N	777586	{26153442,30464555,29098786}	Inadequate	\N	CYP2C19*31 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C19*31 demonstrated decreased enzyme activity compared to wildtype with mephenytoin, omeprazole, voriconazole, and nebivolol substrates (26153442, 30464555, 29098786). Consensus was not achieved among experts as data were sparse and not consistent among substrates. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00019440125, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778141	379	CYP2D6	*111	\N	Uncertain function	\N	n/a	778140	{31368850}	Inadequate	\N	CYP2D6*111 is assigned uncertain function. CYP2D6*111 is defined by a SNP which in silico studies predict to be a deleterious amino acid change (31368850). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": 0.0, "European": 0.004, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.008, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777435	384	CYP2B6	*7	Decreased function	Decreased function	\N	\N	777434	{12642465,14551287,18171905,21659470,24260284,30201214,31324697,32238417,35538637,3553863}	Limited	\N	CYP2B6*7 (c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R and c.1459C>T, p.R487C) - Decreased function: CYB2B6*7 is assigned decreased function. CYP2B6*7 contains the variants which define CYP2B6*6 in addition to a third SNP (c.1459C>T). Since this is a rare variant, there are no data from human liver microsomes or clinical trials regarding its function. Data from several in vitro expression systems are inconclusive: some studies show decreased activity (31324697, 32238417, 3553863) while others exhibit increased activity (12642465, 21659470, 30201214). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. As is the same for *6, the mechanism for decreased activity is aberrant splicing caused by c.516G>T, which leads to reduced amounts of protein and thus, activity (14551287, 18171905, 24260284). As a result, alleles having c.516G>T are considered decreased function, regardless of the functional status of additional other variants unless these cause no function (e.g., CYP2B6*13 and CYP2B6*38). Therefore, the consensus among experts was decreased function based on the presence of c.516G>T and limited evidence.	{"Latino": 0.008, "European": 0.024807692, "Oceanian": 0.01, "East Asian": 0.0, "Near Eastern": 0.024, "Central/South Asian": null, "Sub-Saharan African": 0.016, "African American/Afro-Caribbean": 0.0}	f
778071	380	CYP2D6	*71	\N	Uncertain function	\N	n/a	778070	{24647041,30366777}	Inadequate	\N	CYP2D6*71 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*71 demonstrated decreased enzyme activity compared to wildtype with various substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": 0.042666666, "East Asian": 0.0020697587, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778963	336	G6PD	Abeno	II/Deficient	II/Deficient	\N	\N	778962	{22293322,22963789,1945893,11271380}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779407	362	TPMT	*6	\N	No function	\N	\N	779406	{9246020,16220112,18708949,30023734,39696474}	Moderate	\N	TPMT*6 is assigned no function based on moderate evidence. Erythrocytes from an individual genotyped TPMT*1/*6 exhibited intermediate enzymatic activity toward 6-MP (9246020). An individual carrying TPMT*6 experienced severe leukopenia following standard azathioprine dosing (39696474). In vitro studies using mammalian cell expression systems demonstrate that TPMT.6 protein expression is substantially decreased compared to TPMT.1 (16220112). Additionally, TPMT.6 exhibited reduced substrate affinity for 6-TG, reduced clearance of 6-TG and 6-MP, and enzymatic activity was decreased by 60-80% in vitro (16220112, 18708949). Recombinant TPMT.6 expressed and purified from bacterial cells exhibited decreased protein stability, however activity was unaffected when using 6-MP as a substrate (30023734). Despite conflicting in vitro evidence, the experts agreed to assign no function based on the available clinical data. Five out of ten variant effect predictors tested by CPIC staff predict that the TPMT*6-defining SNV, c.539A>T (p.Y180F), impairs protein function.	{"Latino": 0.00002916, "European": 0.0, "East Asian": 0.0022042317, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
5998159	28	CYP2D6	*178	\N	\N	\N	\N	5998158	\N	\N	\N	\N	\N	f
5998161	28	CYP2D6	*179	\N	\N	\N	\N	5998160	\N	\N	\N	\N	\N	f
5998163	28	CYP2D6	*180	\N	\N	\N	\N	5998162	\N	\N	\N	\N	\N	f
5998165	28	CYP2D6	*181	\N	\N	\N	\N	5998164	\N	\N	\N	\N	\N	f
5998167	28	CYP2D6	*182	\N	\N	\N	\N	5998166	\N	\N	\N	\N	\N	f
5998169	28	CYP2D6	*183	\N	\N	\N	\N	5998168	\N	\N	\N	\N	\N	f
5998171	28	CYP2D6	*184	\N	\N	\N	\N	5998170	\N	\N	\N	\N	\N	f
5998173	28	CYP2D6	*185	\N	\N	\N	\N	5998172	\N	\N	\N	\N	\N	f
777551	384	CYP2C19	*10	\N	Decreased function	\N	\N	777550	{12464799,19661214,21325430,25001882,24945780,21692664}	Limited	\N	CYP2C19*10 is assigned decreased function based on limited evidence.Six in vitro studies using different cell systems found CYP2C19*10 demonstrated decreased enzyme activity compared to wildtype with mephenytoin, omeprazole, and clopidogrel substrates (12464799, 19661214, 21325430, 25001882, 24945780). Another study found CYP2C19*10 exhibited significantly reduced catalytic activities compared with CYP2C19*1 across multiple substrates (21692664). Therefore, consensus among experts was decreased function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.0012398496, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.00010471204, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0032672414}	f
3318602	133	CYP4F2	*16	\N	\N	\N	\N	3318601	\N	\N	\N	\N	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778362	371	DPYD	c.868A>G	Decreased function	Decreased function	\N	0.5	778361	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.00033666822, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.002017857, "African American/Afro-Caribbean": 0.0}	f
3685735	175	RYR1	c.8654C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685734	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685931	175	RYR1	c.14510delA	Likely Benign	Normal function	\N	n/a	3685930	{35849058}	\N	\N	PS4_Sup, BS2_Mod, BS3_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779239	363	RYR1	c.14512C>G	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	779238	{33767344}	\N	\N	PS3_Sup, PS4_Mod, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777439	384	CYP2B6	*9	Decreased function	Decreased function	\N	\N	777438	{11243870,14551287,15622315,18171905,21659470,22927450,23080225,24260284,30085944,30201214,3090656,32238417,35538637,30906561}	Strong	\N	CYP2B6*9 (c.516G>T, p.Q172H/splice defect) - Decreased function: CYP2B6*9 is assigned decreased function. When c.516G>T occurs alone, it defines CYP2B6*9. The c.516G>T variant causes aberrant splicing (14551287, 18171905, 24260284) and is in high linkage disequilibrium with c.785A>G, which is part of the CYP2B6*6 haplotype. c.516G>T is also present in several other haplotypes (e.g., CYP2B6*7, *13, *19, *20, *26, *34, *36, *37 and *38). These haplotypes make it difficult to ascertain the presence of *9 and its clinical function. Although several studies have reported a significant association between c.516G>T and efavirenz exposure (over 3-fold increase) in patient plasma and/or hair samples (15622315, 22927450, 23080225), these associations were erroneously attributed to CYP2B6*9 rather than *6. Several in vitro studies using cDNA expression systems show that CYP2B6*9 decreases activity towards efavirenz, bupropion, methadone, ketamine, and nicotine (21659470, 30085944, 30906561, 32238417, 35538637), while others have shown no or increased activity (11243870, 30201214). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. At present, functional information is informed by the fact that alleles with c.516G>T (e.g., CYP2B6*6) have been associated with decreased function (see description for CYP2B6*6 allele). Therefore, consensus among experts was decreased function based on strong evidence.	{"Latino": 0.07266471, "European": 0.0147, "Oceanian": 0.01, "East Asian": 0.034411334, "Near Eastern": 0.102, "Central/South Asian": 0.059, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.046484537}	f
777471	384	CYP2B6	*26	Decreased function	Decreased function	\N	\N	777470	{17918089,30085944,30201214,32238417,34100292,18171905,24260284}	Limited	\N	CYP2B6*26 (c.499C>G, p.P167A; c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R) – Decreased function: CYP2B6*26 is assigned decreased function. CYP2B6*26 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information). One study evaluating efavirenz plasma concentrations among patients with HIV found CYP2B6*26 was associated with elevated efavirenz concentrations compared to the *1 reference and has similar function to CYP2B6*6. This was demonstrated by similar efavirenz concentrations among CYP2B6 *6/*26 subjects CYP2B6 *6/*6 subjects (17918089). Although one in vitro study using a cDNA expression system found that CYP2B6*26 demonstrated increased enzyme activity compared to the *1 reference (30201214), the experts did not find these results convincing as it has previously been shown that in vitro expression systems may not adequately reflect CYP2B6*6 expression and function, and therefore also not be a suitable system to assess CYP2B6*26. As is the same for *6, the mechanism for decreased activity is aberrant splicing caused by c.516G>T, which leads to reduced amounts of protein and thus, activity (14551287, 18171905, 24260284). As a result, alleles having c.516G>T are considered decreased function, regardless of the functional status of additional other variants unless these cause no function (e.g., CYP2B6*13 and CYP2B6*38). Therefore, the consensus among experts was decreased function based on the presence of c.516G>T and limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
2899145	173	CYP2B6	*40	Decreased function	Decreased function	\N	\N	2899144	{14551287,18171905,24260284,38596098}	Limited	\N	CYP2B6*40 (c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R; c.1133G>A, p.R378Q) – Decreased function: CYP2B6*40 is assigned decreased function. CYP2B6*40 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information). As is the same for *6, the mechanism for decreased activity is aberrant splicing caused by c.516G>T, which leads to reduced amounts of protein and thus, activity (14551287, 18171905, 24260284). As a result, alleles having c.516G>T are considered decreased function, regardless of the functional status of additional other variants unless these cause no function (e.g., CYP2B6*13 and CYP2B6*38). A single in vitro study reported decreased function for p.R378Q using buproprion and efavirez as probes (38596098). Therefore, the consensus among experts was decreased function based on the presence of c.516G>T and limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778975	336	G6PD	Munich	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778974	{22293322,17637841}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": 0.000010226099, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685835	175	RYR1	c.12121C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685834	{35849058}	\N	\N	BP4	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6481191	30	NAT2	*1	Rapid	Increased function	\N	\N	6481190	{9154882,30564082,15558239,10744128,22092036,20040334,9333101,17011540,24444407,20801937,24221535,27223070,10762005,21946899}	Definitive	\N	NAT2*1 is assigned increased function based on definitive evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the reference NAT2*1 allele as "rapid". Under the CPIC allele function terminology, rapid acetylation alleles are categorized as "Increased Function". NAT2*1 corresponds to the NCBI reference sequence, NG_012246.1, containing no SNVs. NAT2*1 has been studied for more than 25 years and has shown rapid acetylation in numerous clinical studies with various substrates. Rapid acetylation activity has been demonstrated in individuals heterozygous for NAT2*1 using caffeine (9333101, 10744128, 15558239, 20801937, 24221535, 27223070), dapsone (10762005), sulfamethazine (21946899), and isoniazid (30149019). NAT2*1 is distinguished from NAT2*4 by the absence of the core SNV c.803G>A (p.R268K).	\N	t
3685909	175	RYR1	c.14210G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685908	{35849058}	\N	\N	PS4, PM1_Sup, PP1_St, PP3_Mod, BS2_Mod, PS3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
2899149	173	CYP2B6	*42	Decreased function	Decreased function	\N	\N	2899148	{14551287,18171905,24260284,38596098}	Limited	\N	CYP2B6*42 (c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R; c.1328G>A, p.R443H) – Decreased function: CYP2B6*42 is assigned decreased function. CYP2B6*42 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information). As is the same for *6, the mechanism for decreased activity is aberrant splicing caused by c.516G>T, which leads to reduced amounts of protein and thus, activity (14551287, 18171905, 24260284). As a result, alleles having c.516G>T are considered decreased function, regardless of the functional status of additional other variants unless these cause no function (e.g., CYP2B6*13 and CYP2B6*38). A single in vitro study reported decreased function for p.R443H using buproprion and efavirez as probes (38596098). Therefore, the consensus among experts was decreased function based on the presence of c.516G>T and limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685889	175	RYR1	c.13990T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685888	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": 0.00001481, "East Asian": null, "Near Eastern": 0.0005784, "Central/South Asian": null, "Sub-Saharan African": null}	f
777563	384	CYP2C19	*16	\N	Decreased function	\N	\N	777562	{15499191,21325430,25001882,21692664}	Limited	\N	CYP2C19*16 is assigned normal function based on limited evidence. A subject with CYP2C19 *2/*16 genotype demonstrated decreased mephobarbital excretion compared to heterozygous CYP2C19 *2 or CYP2C19*3 subjects but greater mephobarbital excretion compared to subjects carrying two no function alleles based on urine metabolites after a 200mg dose (15499191). Two in vitro studies using different cell systems found CYP2C19*16 had nondetectable or decreased enzyme activity compared to wildtype with mephenytoin, omeprazole, and clopidogrel substrates (25001882, 21325430). Another study found CYP2C19*16 exhibited significantly reduced catalytic activities compared with CYP2C19*1 across multiple substrates (21692664).Therefore, consensus among experts was decreased function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
1002698	356	SLCO1B1	*43	\N	Unknown function	\N	\N	1002697	{}	No evidence	\N	SLCO1B1*43 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779473	362	TPMT	*39	\N	No function	\N	\N	779472	{27703193}	Limited	\N	TPMT*39 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*39 exhibited intermediate enzymatic activity and the patient was started on a reduced dose of thiopurines but continued to experience side effects (27703193). TPMT.39 expressed in mammalian cells exhibited decreased protein abundance relative to TPMT.1 (29785012) Eight out of ten variant effect predictors tested by CPIC staff predict that the TPMT*39-defining SNV, c.218C>T (p.A73V), impairs protein function.	{"Latino": 0.0, "European": 0.000006562125, "East Asian": 0.000106, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6481275	30	NAT2	*59	Slow	Decreased function	\N	\N	6481274	{18680467}	Moderate	\N	NAT2*59 is assigned decreased function based on moderate evidence. NAT2*59 is characterized by the core SNVs c.475T>A (p.W159R), c.803G>A (p.R268K), and c.857G>A (p.G286E). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.475T>A (p.W159R). Eight out of ten variant effect predictors tested by CPIC staff predict that c.475T>A (p.W159R) impairs protein function. c.857G>A (p.G286E) defines NAT2*7 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Ten out of ten variant effect predictors tested by CPIC staff predict that c.857G>A (p.G286E) is neutral for protein function. However, published in silico modeling indicates that c.857G>A (p.G286E) disrupts the size/shape of the protein's active site (18680467). Thus, NAT2*59 is assigned decreased function based on c.857G>A. Despite this, the combinatorial effects associated with c.475T>A and c.857G>A are uncertain.	\N	f
777265	384	CACNA1S	c.520C>T	Uncertain function	Malignant Hyperthermia associated	\N	\N	777264	{19825159,28259615,22547813}	\N	\N	19825159: positive in vitro contracture test (biopsied muscle strips) (IVCT); 28259615: positive IVCT; 22547813: R174W mutation does not alter the voltage dependence of EC coupling, indicating that this mutation does not shift the equilibrium of RyR1 toward the activated state. R174W mutation alters the resting conformation of CACNA1S such that it no longer suppresses resting calcium leak via RYR1 and R174W mutation also serves to amplify this resting leak. R174W mutation disrupts the ability of CACNA1S to repress resting calcium leak from SR via RYR1 leading t elevated resting myoplasmic calcium and increased sensitivity to MH triggers	{"Latino": 0.00005783, "European": 0.000014776972, "East Asian": 0.0001087, "Near Eastern": 0.0, "Central/South Asian": 0.00003267}	f
777805	366	CYP2C9	*69	Uncertain function	Uncertain function	\N	n/a	777804	{33536773}	Inadequate evidence	\N	CYP2C9*69 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variant present in CYP2C9*69 is predicted to be deleterious in both SIFT and Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779495	363	UGT1A1	*28	\N	Decreased function	\N	\N	779494	{9653159,15179405}	\N	\N	15179405: SNS-38 (in vivo) - based on protein quantification	{"Latino": 0.4, "European": 0.31647462, "Oceanian": 0.043209877, "East Asian": 0.14802907, "Near Eastern": 0.30762586, "Central/South Asian": 0.41421428, "Sub-Saharan African": 0.40004247, "African American/Afro-Caribbean": 0.37335765}	f
779499	362	UGT1A1	*37	\N	Decreased function	\N	\N	779498	{9653159}	\N	\N	\N	{"Latino": 0.0, "European": 0.00068587105, "Oceanian": 0.0, "East Asian": 0.0, "Near Eastern": 0.004330254, "Central/South Asian": 0.0, "Sub-Saharan African": 0.037069373, "African American/Afro-Caribbean": 0.057007298}	f
6970386	14	SLCO1B1	*55	\N	\N	\N	\N	6970385	\N	\N	\N	\N	\N	f
6970388	14	SLCO1B1	*56	\N	\N	\N	\N	6970387	\N	\N	\N	\N	\N	f
6970390	14	SLCO1B1	*57	\N	\N	\N	\N	6970389	\N	\N	\N	\N	\N	f
6970392	14	SLCO1B1	*58	\N	\N	\N	\N	6970391	\N	\N	\N	\N	\N	f
777312	234	CFTR	3272-26A->G	\N	ivacaftor responsive	\N	\N	777311	{}	\N	\N	\N	\N	f
777318	234	CFTR	A1067T	\N	ivacaftor responsive	\N	\N	777317	{}	\N	\N	\N	\N	f
777320	234	CFTR	A455E	\N	ivacaftor responsive	\N	\N	777319	{}	\N	ACMG screening panel	\N	\N	f
777330	234	CFTR	D579G	\N	ivacaftor responsive	\N	\N	777329	{}	\N	\N	\N	\N	f
777336	234	CFTR	E831X	\N	ivacaftor responsive	\N	\N	777335	{}	\N	\N	\N	\N	f
777350	234	CFTR	G551D	\N	ivacaftor responsive	\N	\N	777349	{}	\N	ACMG screening panel	\N	\N	f
777352	234	CFTR	G551S	\N	ivacaftor responsive	\N	\N	777351	{}	\N	\N	\N	\N	f
777380	234	CFTR	S549R(A>C)	\N	ivacaftor responsive	\N	\N	777379	{}	\N	\N	\N	\N	f
778923	336	G6PD	Calvo Mackenna	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778922	{22293322,7655862}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779481	142	TPMT	*43	\N	No function	\N	\N	779480	{31005613,32865889}	Limited	\N	TPMT*43 is assigned no function based on limited evidence. TPMT*43 results in a splicing defect and the loss of exon 5, producing a non-functional enzyme (31005613, 32865889). Erythrocytes from an individual genotyped TPMT*1/*43 exhibited intermediate enzymatic activity (31005613, 32865889). Ten out of ten variant effect predictors tested by CPIC staff predict that the TPMT*43-defining SNVs, c.234G>T (p.W78C) and c.262G>A (p.G88S), impair protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777789	384	CYP2C9	*61	Decreased function	Decreased function	\N	0.5	777788	{30518301}	Limited	\N	CYP2C9*61 is assigned decreased function based on limited evidence in a heterozygous patient. CYP2C9*61 was first described in a patient requiring a low daily warfarin dose of 3mg (30518301). CYP2C9*61 is defined by two SNPs, one of which is the defining SNP for CYP2C9*2. Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the function of this allele is similar to CYP2C9*2 and phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1103380	286	CYP2D6	*147	\N	Uncertain function	\N	n/a	1103379	{}	Inadequate	\N	CYP2D6*147 is assigned uncertain function due to inadequate evidence. CYP2D6*147 is defined by the insertion of three amino acids found in CYP2D6*30 (for which the function is uncertain) and the 100C>T variant which has been shown to cause severely decreased function of e.g. *10. Therefore, consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778763	336	G6PD	Cairo	II/Deficient	II/Deficient	\N	\N	778762	{22293322,1945893,22770933}	Moderate	\N	WHO Class II assigned based on evidence supporting decreased enzyme activity (less than A-). Additionally, analysis of the clinical presentation of the 11 children with G6PD Cairo revealed that all suffered hemolytic crises due to fava bean consumption and reported varying levels of jaundice at birth. The resulting in a WHO class II assignment (22770933).	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
777677	384	CYP2C9	*5	Decreased function	Decreased function	\N	0.5	777676	{23752738,15289788,11455026,16220110,17504998,21811894,11901091}	Strong	\N	CYP2C9*5 is assigned decreased function based on strong evidence in heterozygous patients and in vitro studies. Three subjects carrying the CYP2C9*5 allele (CYP2C9*1/*5, CYP2C9*5/*6, CYP2C9*5/*8 genotype) had decreased losartan metabolism compared to wildtype based on urinary metabolites after a single 25mg dose (15289788). Two CYP2C9 *1/*5 subjects, one CYP2C9 *5/*6 subject, and one CYP2C9*5/*8 subject had lower phenytoin metabolism compared to wildtype based on urinary excretion of a phenytoin metabolite after a single 300mg dose. Additionally, the CYP2C9 *5/*6 subject demonstrated the lowest phenytoin metabolism as the only subject of the 109 subject cohort to have a urinary metabolite concentration below the limit of quantification (16220110). One CYP2C9 *5/*8 demonstrated the lowest acenocoumarol metabolism based on plasma concentrations in a 36 subject cohort (21811894). One CYP2C9*1/*5 subject demonstrated decreased indisulam metabolism with an AUC nearly two times greater than wildtype subjects (17504998). These results correlated with in vitro pharmacokinetic studies which demonstrated decreased clearance of warfarin, diclofenac, flurbiprofen, naproxen, and piroxicam compared to wildtype (11455026, 11901091). A separate in vitro study found CYP2C9*5 has decreased enzyme activity compared to wildtype with warfarin and tolbutamide substrates that (23752738). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on strong evidence.	{"Latino": 0.00871987, "American": 0.0014913112, "European": 0.00017448276, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.00052266667, "Central/South Asian": 0.0, "Sub-Saharan African": 0.010325842, "African American/Afro-Caribbean": 0.011626912}	f
777537	384	CYP2C19	*3	\N	No function	\N	\N	777536	{7969038,9103550,22027650}	Definitve	\N	CYP2C19*3 is assigned no function based on definitive evidence. CYP2C19*3 has been studied for more than 20 years and its association with impaired function is well-established (7969038, 9103550, 22027650). CYP2C19*3 is defined by an early stop codon resulting in a truncated protein lacking a heme binding region and a majority of the substrate binding region, making it a nonfunctional protein. CYP2C19*3 was first identified in a homozygous subject demonstrating decreased mephenytoin metabolism and was subsequently identified in six additional subjects demonstrating decreased mephenytoin metabolism (7969038).	{"Latino": 0.00082841824, "American": 0.00035169988, "European": 0.0016180738, "Oceanian": 0.14638089, "East Asian": 0.07247335, "Near Eastern": 0.016479162, "Central/South Asian": 0.015685236, "Sub-Saharan African": 0.0026677323, "African American/Afro-Caribbean": 0.0027567567}	f
779489	364	UGT1A1	*1	\N	Normal function	\N	\N	779488	{7565971,9653159,15179405}	\N	\N	15179405: SNS-38 (in vivo) - based on protein quantification	{"Latino": 0.20571208, "European": 0.36072147, "Oceanian": 0.95679015, "East Asian": 0.7056254, "Near Eastern": 0.6801109, "Central/South Asian": 0.5409231, "Sub-Saharan African": 0.4930486, "African American/Afro-Caribbean": 0.03087449}	t
778011	380	CYP2D6	*39	\N	Normal function	\N	1.0	778010	{18784265,11266079,24647041,30366777}	Limited	\N	CYP2D6*39 is assigned normal function based on limited evidence. A liver microsomes sample of a subject with CYP2D6 *10/*39 genotype demonstrated similar enzyme activity compared to wildtype with a bufuralol substrate (11266079). Similarly, in vitro studies found CYP2D6*39 demonstrated similar enzyme activity compared to wildtype with bufuralol, dextromethorphan, and tamoxifen substrates (18784265, 24647041). Although one in vitro study found CYP2D6*39 demonstrated decreased clearance compared to wildtype with a primaquine substrate (30366777) the experts did not find this result convincing as CYP2D6*39 demonstrated similar activity compared to wildtype towards a majority of substrates. Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence.	{"Latino": 0.008, "American": 0.001, "European": 0.014010031, "Oceanian": 0.0063141957, "East Asian": 0.0056442493, "Near Eastern": 0.026844444, "Central/South Asian": 0.0033921853, "Sub-Saharan African": 0.00080620806, "African American/Afro-Caribbean": 0.020066908}	f
778021	380	CYP2D6	*44	\N	No function	\N	0.0	778020	{15618746}	Limited	\N	CYP2D6*44 is assigned no function based on limited evidence in a heterozygous subject. CYP2D6*44 was identified in a subject with CYP2D6 *2/*44 genotype demonstrating decreased dextromethorphan metabolism compared to CYP2D6 *1/*2 subjects (15618746). CYP2D6*44 is defined by a splicing defect yielding a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.00041258382, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778009	380	CYP2D6	*38	\N	No function	\N	0.0	778008	{9918137}	Limited	\N	CYP2D6*38 is assigned no function based on limited evidence in a heterozygous subject. CYP2D6*38 was identified in a heterozygous subject with CYP2D6 *4/*38 genotype demonstrating poor metabolism with a debrisoquine substrate (9918137). CYP2D6*38 is defined by a four base pair deletion resulting in a frameshift. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778939	336	G6PD	Beverly Hills, Genova, Iwate, Niigata, Yamaguchi	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778938	{22293322,7440223,2307454,9192788}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778947	336	G6PD	Wisconsin	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778946	{22293322,16934959,7655862}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779021	336	G6PD	Yunan	Uncertain function	Uncertain function	\N	\N	779020	{22293322,11780463}	Inadequate	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778667	337	G6PD	B (reference)	IV/Normal	IV/Normal	\N	\N	778666	{22293322,2572288}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.9772377, "European": 0.99463695, "East Asian": 0.97378683, "Central/South Asian": 0.9557555, "African American/Afro-Caribbean": 0.55657554}	t
778817	336	G6PD	Cincinnati	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778816	{22293322,20949590}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778805	336	G6PD	Coimbra Shunde	II/Deficient	II/Deficient	\N	\N	778804	{22293322,1551674,8471773}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.000010230493, "East Asian": 0.00007214487, "Central/South Asian": 0.00020966558, "African American/Afro-Caribbean": 0.0}	f
777477	384	CYP2B6	*29	Decreased function	Decreased function	\N	\N	777476	{17885627,28181240}	Limited	\N	CYP2B6*29 (CYP2B7-CYP2B6 hybrid gene) – Decreased function: CYP2B6*29 is assigned decreased function. This allele is a hybrid consisting of CYP2B7 (exons 1-4) and CYP2B6 (exons 5-9) harboring 23 amino acid changes compared to the protein encoded by the CYP2B6*1 reference. Among those is c.516G>T which is one of the function-altering variants defining CYP2B6*6. CYP2B6*29 was identified in a subject with an elevated efavirenz AUC compared to the *1 reference and similar to those seen in patients carrying one decreased function allele (17885627). One in vitro study found that primary human hepatocytes of subjects with a CYP2B6*29 allele had slightly lower protein expression and enzyme activity compared to the *1 reference (28181240). The same study also showed that the AUC for 4-OH-cyclophosphamide was significantly lower for patients with a CYP2B6*1/*29 genotype compared to *1/*1 (28181240). Therefore, consensus among experts was decreased function based on limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778891	336	G6PD	Insuli	IV/Normal	IV/Normal	\N	\N	778890	{22293322,12737940}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
777679	384	CYP2C9	*6	No function	No function	\N	0.0	777678	{23752738,15289788,11740344,16220110,17895500,21811894,15094935}	Strong	\N	CYP2C9*6 is assigned no function based on strong supporting evidence in heterozygous and homozygous patients. This allele was first identified in a CYP2C9*6/*6 patient experiencing phenytoin toxicity after recently starting the medication. Based on serial phenytoin plasma concentrations after discontinuing phenytoin, the patient had an estimated 17% phenytoin clearance compared to wildtype (11740344). In a separate case report, a patient with CYP2C9*6/*6 genotype stable on a low weekly warfarin dose demonstrated impaired warfarin metabolism with an S:R warfarin ratio 6x greater than expected (15094935). The S:R warfarin ratio of this patient was the highest among 52 patients on a stable dose of warfarin with a CYP2C9 genotype of *1/*1, *1/*2, *1/*3, *2/*2, or *2/*3 (17895500). Two subjects (CYP2C9*1/*6 and CYP2C9*5/*6 genotype, respectively) had decreased losartan metabolism compared to wildtype subjects based on urinary metabolites after a single 25mg dose (15289788). Three CYP2C9*1/*6 subjects and one CYP2C9*5/*6 subjects had lower phenytoin metabolism compared to wildtype based on urinary excretion of a phenytoin metabolite after a single 300mg dose. Additionally, the CYP2C9*5/*6 subject demonstrated the lowest phenytoin metabolism as the only subject of the 109 subject cohort to have a urinary metabolite concentration below the limit of quantification (16220110). CYP2C9*6 is defined by a deletion resulting in a frameshift and not included in in vitro studies as it is it is a null allele resulting in no protein formation (23752738). Although one CYP2C9*1/*6 subject had a similar acenocoumarol metabolite plasma concentration compared to wildtype subjects 8 and 24 hours after a single 8mg dose (21811894), the experts did not deem this result as convincing conflicting evidence based on the small sample size. Therefore, consensus among experts was no function with an activity value of 0 based on strong evidence.	{"Latino": 0.0009750473, "American": 0.0, "European": 0.00028025627, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.008801762, "African American/Afro-Caribbean": 0.008521383}	f
778821	336	G6PD	Radlowo	II/Deficient	II/Deficient	\N	\N	778820	{22293322,10571945}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3564277	187	G6PD	Telti, Kobe	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	3564276	{22293322,7327562}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778689	336	G6PD	Kambos	III/Deficient	III/Deficient	\N	\N	778688	{22293322,15223006}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
777589	384	CYP2C19	*32	\N	Uncertain function	\N	\N	777588	{26153442,30464555,29098786}	Inadequate	\N	CYP2C19*32 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C19*32 demonstrated enzyme activity ranging from decreased to similar activity compared to wildtype with various substrates (26153442, 30464555, 29098786). Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00017527216, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777691	384	CYP2C9	*12	Decreased function	Decreased function	\N	0.5	777690	{15284535,23752738,28758225,23688605}	Limited	\N	CYP2C9*12 is assigned decreased function based on limited evidence in heterozygous patients and in vitro studies. Four patients on a stable dose of warfarin with CYP2C9*1/*12 genotype required a lower weekly warfarin dose compared to CYP2C9*1/*1 patients (23688605). In vitro studies similarly found CYP2C9*12 demonstrated decreased enzyme activity with warfarin and tolbutamide substrates compared to wildtype (23752738, 15284535, 28758225). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00041809047, "Near Eastern": 0.001, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777695	384	CYP2C9	*14	Decreased function	Decreased function	\N	0.5	777694	{16099926,23844998,24118918,25142737,25144335,25476996,25951663,25832633,25884291,25924705,27163851,24077631,24956244,19077919,15371982,23752738}	Moderate	\N	CYP2C9*14 is assigned decreased function based on moderate evidence in heterozygous patients and in vitro studies. Separate studies of patients on a stable dose of warfarin with CYP2C9 *1/*14 genotype required a lower warfarin dose compared to CYP2C9*1/*1 patients (24956244, 19077919, 15371982). The VKORC1 and CYP4F2 variants associated with increased warfarin dose requirements were also observed in one of these patients which further suggested decreased warfarin metabolism and warfarin dose was due to the CYP2C9 *1/*14 genotype (24956244). In vitro studies similarly found CYP2C9*14 demonstrated decreased clearance of warfarin, phenytoin, tolbutamide, glimepiride, carvedilol, propofol, flurbiprofen, mestranol, diclofenac, and losartan (23752738, 27163851, 16099926, 24077631, 24118918, 25476996, 25832633, 25144335, 25924705, 25951663, 23844998). Although two in vitro studies showed CYP2C9*14 had similar activity compared to wildtype, the experts did not find these results convincing as in these studies CYP2C9*2 and/or CYP2C9*3 which definitively have decreased function and no function, respectively, demonstrated increased activity compared to wildtype in these studies (25142737, 25884291). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on moderate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00033588216, "Near Eastern": 0.001, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779005	336	G6PD	Figuera da Foz	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	779004	{22293322,18056001}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778945	336	G6PD	Krakow	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778944	{22293322,18066402}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779027	336	G6PD	Laibin	Uncertain	Uncertain function	\N	\N	779026	{22293322,17018380}	Inadequate	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778825	336	G6PD	North Dallas	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778824	{22293322,1945893}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778863	336	G6PD	Papua	Uncertain	Uncertain function	\N	\N	778862	{22293322,9410474}	Inadequate	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778683	336	G6PD	Rignano	III/Deficient	III/Deficient	\N	\N	778682	{22293322,17524386}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
5997309	28	CYP2B6	*50	\N	\N	\N	\N	5997308	\N	\N	\N	\N	\N	f
777535	384	CYP2C19	*2	\N	No function	\N	\N	777534	{8195181,22027650}	Definitve	\N	CYP2C19*2 is assigned no function based on definitive evidence. CYP2C19*2 has been studied for more than 20 years and its association with impaired function is well-established (8195181, 22027650). CYP2C19*2 is defined by splicing defects resulting in a truncated protein lacking a heme binding region, making it a nonfunctional protein. CYP2C19*2 was first identified in a homozygous subject demonstrating decreased mephenytoin metabolism and was subsequently identified in seventeen additional subjects demonstrating decreased mephenytoin metabolism (8195181). Therefore, consensus among experts was no function based on definitive evidence.	{"Latino": 0.104187496, "American": 0.121365316, "European": 0.14685704, "Oceanian": 0.6095202, "East Asian": 0.28352264, "Near Eastern": 0.11984708, "Central/South Asian": 0.269916, "Sub-Saharan African": 0.15684253, "African American/Afro-Caribbean": 0.18149492}	f
777459	384	CYP2B6	*20	Decreased function	Decreased function	\N	\N	777458	{16272958,21746968,30201214,18171905,24260284}	Limited	\N	CYP2B6*20 (c.503C>T, p.T168I; c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R) – Decreased function: CYP2B6*20 is assigned decreased function. CYP2B6*20 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information). Three in vitro studies using cDNA expression systems found decreased enzyme activity of CYP2B6*20 compared to the *1 reference with various substrates (16272958, 21746968, 30201214). As is the same for *6, the mechanism for decreased activity is aberrant splicing caused by c.516G>T, which leads to reduced amounts of protein and thus, activity (14551287, 18171905, 24260284). As a result, alleles having c.516G>T are considered decreased function, regardless of the functional status of additional other variants unless these cause no function (e.g., CYP2B6*13 and CYP2B6*38). Therefore, the consensus among experts was decreased function based on the presence of c.516G>T and limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.016, "African American/Afro-Caribbean": 0.0}	f
777699	384	CYP2C9	*16	Decreased function	Decreased function	\N	0.5	777698	{16099926,24077631,24118918,24464553,25142737,25951663,25144335,25476996,25614704,25832633,25884291,25924705,27163851,23844998}	Limited	\N	CYP2C9*16 is assigned decreased function based on limited evidence in a heterozygous patient and in vitro studies. One subject with CYP2C9*1/*16 genotype exhibited decreased clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose. This result correlated with the in vitro study where CYP2C9*16 demonstrated similar enzyme expression but 3.4% enzyme activity with a tolbutamide substrate compared to wildtype (25614704). Multiple in vitro studies similarly found CYP2C9*16 demonstrated decreased clearance with various substrates compared to wildtype (16099926, 24077631, 24118918, 24464553, 25951663, 25144335, 25476996, 25832633, 25884291, 25924705, 27163851, 23844998). Although one in vitro study showed CYP2C9*16 had similar activity compared to wildtype, the experts did not find this result convincing as in this study CYP2C9*2 and CYP2C9*3 which definitively have decreased function and no function, respectively, demonstrated increased activity compared to wildtype (25142737). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.001877621, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777721	384	CYP2C9	*27	Uncertain function	Uncertain function	\N	n/a	777720	{23752738,16788382,23844998,24118918,25142737,25144335,25951663,25476996,25614704,25832633,25884291,25924705,27163851,24077631}	Inadequate evidence	\N	CYP2C9*27 is assigned uncertain function due to inadequate evidence. One subject with CYP2C9 *1/*27 genotype exhibited similar clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704). In vitro studies showed conflicting results with CYP2C9*27 exhibiting enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24118918, 23844998, 25476996, 25832633, 24077631, 25144335, 25951663, 23752738, 16788382, 25884291, 25614704, 25924705, 27163851, 25142737). Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0016176943, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778669	336	G6PD	No name	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778668	{22293322,32387609,21446359}	Inadequate	\N	Function assigned based on evidence supporting complete loss of enzyme activity (32387609)	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
777749	384	CYP2C9	*41	Uncertain function	Uncertain function	\N	n/a	777748	{24077631,24118918,25142737,25951663,25144335,25476996,25614704,25832633,25884291,25924705,27163851,23844998}	Inadequate evidence	\N	CYP2C9*41 is assigned uncertain function due to inadequate evidence in one heterozygous subject and in vitro studies. One subject with CYP2C9 *1/*41 genotype exhibited increased AUC but similar oral clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704). In vitro studies found CYP2C9*41 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25951663, 25476996, 25832633, 25884291, 25924705, 27163851, 23844998, 25614704). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778921	336	G6PD	Montpellier	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778920	{22293322,22139979}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.000027188444, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778933	336	G6PD	Madrid	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778932	{22293322,9332310}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778877	336	G6PD	Omiya	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778876	{22293322,1945893}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778955	336	G6PD	Puerto Limon	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778954	{22293322,7160841}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779103	142	NUDT15	*20	\N	Uncertain function	\N	\N	779102	{32094176}	Inadequate	\N	NUDT15*20 is assigned uncertain function based on inadequate evidence. An in vitro study expressed NUDT15*20 in HEK293 cells and found NUDT15 protein expression and thiopurine sensitivity were comparable to cells expressing NUDT15*1 (32094176). Eight out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*20-defining SNV (c.386C>G (p.P129R)) impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
777939	380	CYP2D6	*2	\N	Normal function	\N	1.0	777938	{7903454,11037799,11266079,12915955,18784265,20456744,24647041,25469868,26310775,26542054,26652007,26937172,26968424,27203132,27251229,27354764,27538917,30366777}	Moderate	\N	CYP2D6*2 is assigned normal function based on moderate evidence. CYP2D6*2 has consistently been described in subjects demonstrating similar metabolism with various CYP2D6 substrates compared to wildtype (7903454, 11037799, 12915955, 20456744). Although in vitro studies found CYP2D6*2 had enzyme activity ranging from similar to decreased activity compared to wildtype, the in vitro data was not convincing as the differences in results may be due to differences in the expression system used (11266079, 18784265, 24647041, 25469868, 26310775, 26542054, 26652007, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917, 30366777). Therefore, consensus among experts was normal function with an activity value of 1 based on moderate evidence.	{"Latino": 0.22684056, "American": 0.217449, "European": 0.18536054, "Oceanian": 0.0611197, "East Asian": 0.1191732, "Near Eastern": 0.19004925, "Central/South Asian": 0.27445427, "Sub-Saharan African": 0.1738963, "African American/Afro-Caribbean": 0.15468602}	f
1777307	288	CYP2D6	*2x≥3	\N	Increased function	\N	≥3.0	777938	{7616439,7903454,8764380}	Limited	\N	CYP2D6*2x≥3 is assigned increased function based on limited evidence. CYP2D6*2x≥3 was described in a family demonstrating increased enzyme activity based on urine metabolites with a debrisoquine substrate (7903454). Subjects with CYP2D6 gene duplications demonstrated increased enzyme activity with the greatest debrisoquine metabolism among all subjects (7616439, 8764380). Therefore, consensus among experts was increased function with an activity value of ≥3 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.00050, "American": 0.0, "European": 0.001, "Oceanian": null, "East Asian": 0.001, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.003, "African American/Afro-Caribbean": 0.0}	f
778971	336	G6PD	Japan, Shinagawa	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778970	{22293322,8193373,1611091}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
777591	384	CYP2C19	*33	\N	Uncertain function	\N	\N	777590	{26153442,30464555,29098786}	Inadequate	\N	CYP2C19*33 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C19*33 demonstrated decreased enzyme activity compared to wildtype with mephenytoin, omeprazole, and voriconazole substrates (26153442, 30464555, 29098786). Consensus was not achieved among experts as data were sparse and not consistent among substrates. Therefore, uncertain function was assigned	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00017527216, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777713	384	CYP2C9	*23	Decreased function	Decreased function	\N	0.5	777712	{23752738,23844998,24118918,25951663,25142737,25144335,25476996,25832633,25884291,25924705,27163851,24077631}	Limited	\N	CYP2C9*23 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*23 demonstrated decreased clearance compared to wildtype (23844998, 24118918, 25144335, 25476996, 23752738, 25832633, 25884291, 25924705, 24077631). Although three in vitro studies showed CYP2C9*23 had similar activity compared to wildtype, the experts did not find these results convincing as in these studies CYP2C9*2 which definitively has decreased function, demonstrated increased or similar activity compared to wildtype in these studies (25142737, 25951663, 27163851). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0002119417, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3827887	157	MT-RNR1	m.839A>G	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827886	{21205314}	Inadequate evidence	\N	MT-RNR1 839A>G is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. Screening of individuals with aminoglycoside-hearing loss identified this variant in one study (21205314). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.00006424638, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null}	f
5881977	41	NUDT15	*21	\N	Uncertain function	\N	\N	5881976	{32094176}	Inadequate	\N	NUDT15*21 is assigned uncertain function based on inadequate evidence. An in vitro study expressed NUDT15*21 in HEK293 cells and found NUDT15 protein expression and thiopurine sensitivity were comparable to cells expressing NUDT15*1 (32094176). Nine out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*21-defining SNV, c.410G>C (p.G137A), is neutral for protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
777763	384	CYP2C9	*48	Uncertain function	Uncertain function	\N	n/a	777762	{24077631,24118918,25142737,25144335,25476996,25614704,25832633,25884291,25951663,25924705,27163851,23844998}	Inadequate evidence	\N	CYP2C9*48 is assigned uncertain function due to inadequate evidence in one heterozygous subject and in vitro studies. One subject with CYP2C9 *1/*48 genotype exhibited increased AUC and decreased oral clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704). In vitro studies found CYP2C9*48 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25951663, 25924705, 27163851, 23844998, 25614704). Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777775	384	CYP2C9	*54	Uncertain function	Uncertain function	\N	n/a	777774	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25951663,25924705,27163851,23844998}	Inadequate evidence	\N	CYP2C9*54 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C9*54 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25951663, 25884291, 25924705, 27163851, 23844998). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779065	364	NUDT15	*1	\N	Normal function	\N	\N	779064	{26878724,28659275,27530327,32094176,34636169,38246006,31645647,37488179,27604507,34480209,35067667,28445187,32372428,33481917,32598049,28903549,32308129,29720126,36858569,35156873,32221476,31507415,27577869,27416873,26033531,32873882,39688234}	Definitive	\N	NUDT15*1 is assigned normal function based on definitive evidence. NUDT15*1 corresponds to the reference sequence, NG_047021.1, containing no SNVs. As such, the protein encoded by this transcript is used as the reference for in vitro (26878724, 28659275, 27530327, 32094176, 34636169, 38246006, preclinical (31645647, 37488179), and clinical studies (27604507, 26878724, 34480209, 35067667, 28445187, 32372428, 33481917, 39688234). Additionally, NUDT15*1/*1 patients have been shown to tolerate standard thiopurine dosing (26878724, 32598049, 28903549, 32308129, 29720126, 36858569, 35156873, 32221476, 31507415, 27577869, 27416873, 26033531, 32873882, 39688234).	{"Latino": 0.9728806, "European": 0.9931303, "East Asian": 0.9137417, "Central/South Asian": 0.93002415}	t
6481279	30	NAT2	*61	\N	Unknown function	\N	\N	6481278	{}	No evidence	\N	NAT2*61 is assigned unknown function based on a lack of evidence. NAT2*61 is characterized by the core SNVs c.506A>G (p.Y169C) and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.506A>G (p.Y169C). Four out of ten variant effect predictors tested by CPIC staff predict that c.506A>G (p.Y169C) impairs protein function.	\N	f
777997	380	CYP2D6	*32	\N	Decreased function	\N	0.25	777996	{24647041,30366777}	Limited	\N	CYP2D6*32 is assigned decreased function with an activity value of 0.25 due to limited evidence. In vitro studies found CYP2D6*32 demonstrated enzyme activity ranging from nondetectable to decreased activity compared to wildtype with various substrates (24647041, 30366777). *32 also contains 2989G>A which is the core SNP of *41 with decreased function and the only other SNP of concern, 3854G>A (E410K) would not be expected to change function as the *27 allele (defined by 3854G>A (E410K)) is normal function. Therefore, consensus among experts was decreased function with limited evidence.	{"Latino": null, "American": 0.0, "European": 0.003, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.002, "Sub-Saharan African": 0.0004385813, "African American/Afro-Caribbean": 0.0}	f
777697	384	CYP2C9	*15	No function	No function	\N	0.0	777696	{16099926,23752738}	Limited	\N	CYP2C9*15 is assigned no function based on limited evidence. CYP2C9*15 is defined by a nonsense mutation which results in a premature stop codon resulting in a significant truncation of the protein. In an in vitro study, CYP2C9*15 did not result in detectable protein expression (16099926). CYP2C9*15 was not included in subsequent in vitro studies because it is a null allele resulting in no protein formation (23752738). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
777953	380	CYP2D6	*9	\N	Decreased function	\N	0.25	777952	{1844820,8101460,11266079,24647041,30366777,32599653,33932135,33792048,33967790,30312494}	Moderate	\N	CYP2D6*9 is assigned decreased function based on moderate evidence. CYP2D6*9 was first identified in a liver sample with decreased protein expression and enzyme activity (1844820). Subjects with CYP2D6*9 demonstrated decreased debrisoquine metabolism but greater metabolism compared to subjects with no function alleles based on urine metabolites, indicating there is not a complete loss of enzyme function (8101460). Similarly, liver microsomes of two subjects with CYP2D6*4/*9 and CYP2D6 *1/*9 genotype demonstrated decreased intrinsic clearance compared to wildtype with a bufuralol substrate (11266079). Two in vitro studies found CYP2D6*9 had a modest decrease in intrinsic clearance compared to wildtype (24647041, 30366777). Although one in vitro experiment found CYP2D6*9 had similar activity compared to wildtype with various substrates, the result was not convincing as decreased protein expression in vivo likely contributes to decreased enzyme activity observed in subjects carrying the CYP2D6*9 allele (1844820). Pharmacogenomic clinical studies found the measured activity values for several substrates is reduced (0.34 (PMID 30312494), 0.18 (PMID 33792048), 0.28 (PMID 33792048), 0.22 (PMID 32599653); 0.46 PMID 33932135) and a lower activity value of 0.25 is warranted for most substrates. Therefore, consensus among experts was decreased function with an activity value of 0.25 based on moderate evidence.	{"Latino": 0.015500509, "American": 0.007059503, "European": 0.02754178, "Oceanian": 0.0, "East Asian": 0.0017375742, "Near Eastern": 0.0038028897, "Central/South Asian": 0.0018789063, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0043313783}	f
6481195	30	NAT2	*5	Slow	Decreased function	\N	\N	6481194	{9154882,8781741,28653770,8102597,30564082,15558239,7668286,1451720,10744128,22092036,1872889,8689813,20040334,17011540,22970273,16531626,15565348,9321764,9110365,31257615,29018032,24702251,24444407,15110095,27509179,11773863,20801937,16003747,21750470,9565293,9891107,24221535,8287065,27223070,8001235,8923605,10762005,8081359,35928262,28752039,17505821,21946899,16570187,15032315,18167504,17434923,33815485,18680467,19336229,15564878,7669073,11337936}	Definitive	\N	NAT2*5 is assigned decreased function based on definitive evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*5 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". The functional SNV c.341T>C (p.I114T) in NAT2*5 has been studied for more than 25 years and has shown decreased N-acetylation activity in numerous clinical and in vitro studies using various substrates. Clinical studies have demonstrated that individuals homozygous for NAT2*5 or heterozygous for NAT2*5 in combination with another decreased function allele exhibit decreased acetylation activity toward caffeine metabolites (8102597, 7668286, 10744128, 9891107, 20801937, 22970273, 24221535, 28653770), isoniazid (9154882, 9321764, 19336229, 35928262) sulfonamides (1872889, 15032315, 16570187, 18167504, 21946899), and dapsone (10762005). Individuals homozygous for NAT2*5 or heterozygous for NAT2*5 in combination with another decreased function allele exhibit increased hydralazine exposure (24702251, 31257615). Five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. In vitro studies show that NAT2*5 exhibits similar thermostability to NAT2*4, which was previously used as the reference allele (8081359, 15564878, 17434923, 11337936), however NAT2*5 is subjected to enhanced protein degradation by the proteasome (15564878), indicating decreased protein levels as the molecular mechanism for the decreased acetylation activity observed.	\N	f
779699	314	CYP2D6	*6x2	\N	No function	\N	0.0	777946	{7894499,7951238}	Limited	\N	CYP2D6*6x2 is assigned no function based on limited evidence. CYP2D6*6 is defined by a single nucleotide deletion resulting in a frameshift and premature stop codon yielding a truncated and nonfunctional protein (7894499). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing a duplication of this allele would be clinically similar to phenotypes comprising the nonduplicated allele.	{"Latino": 0.00011035591, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.000067795685}	f
777959	380	CYP2D6	*12	\N	No function	\N	0.0	777958	{8655150,9241659,24647041,30366777}	Limited	\N	CYP2D6*12 is assigned no function based on limited evidence. CYP2D6*12 is defined by a nonsense mutation yielding a nonfunctional enzyme and was identified in a subject demonstrating markedly decreased sparteine metabolism (8655150, 9241659). Two in vitro studies found CYP2D6*12 had nondetectable enzyme activity with various substrates (24647041, 30366777). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": 0.0063913045, "European": 0.00013778963, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.002101211, "African American/Afro-Caribbean": 0.00066490064}	f
778109	380	CYP2D6	*95	\N	Uncertain function	\N	n/a	778108	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*95 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*95 demonstrated enzyme activity ranging from similar to decreased activity compared to wildtype with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). Therefore, consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777991	380	CYP2D6	*29	\N	Decreased function	\N	0.5	777990	{11470994,11823760,24647041,30366777}	Moderate	\N	CYP2D6*29 is assigned decreased function based on moderate evidence in homozygous subjects and in vitro studies. Three subjects with CYP2D6*29/*29 genotype demonstrated decreased metabolism compared to CYP2D6*1/*29 subjects with a debrisoquine substrate (11470994). Similarly, four subjects with CYP2D6*29/*29 genotype demonstrated decreased metabolism compared to wildtype with dextromethorphan and metoprolol substrates (11823760). Multiple in vitro studies found CYP2D6*29 had decreased enzyme activity compared to wildtype with various substrates (11470994, 24647041, 30366777). Although one study found subjects with CYP2D6*29/*29 genotype demonstrated similar metabolism compared to wildtype with debrisoquine and codeine substrates (11823760) the experts did not find this result convincing due to the small sample size. Therefore, consensus among experts with decreased function with an activity value of 0.5 based on moderate evidence.	{"Latino": 0.0152478125, "American": 0.0020174354, "European": 0.0010464214, "Oceanian": 0.0, "East Asian": 0.000097904944, "Near Eastern": 0.0077560195, "Central/South Asian": 0.0016065163, "Sub-Saharan African": 0.10825595, "African American/Afro-Caribbean": 0.08743822}	f
777995	380	CYP2D6	*31	\N	No function	\N	0.0	777994	{15726636,20473659,24647041,30366777}	Moderate	\N	CYP2D6*31 is assigned no function based on moderate evidence in heterozygous subjects and in vitro studies. CYP2D6*31 was first identified in a subject with CYP2D6 *4/*31 genotype demonstrating markedly decreased metoprolol metabolism with an AUC more than three times greater than the AUC of wildtype subjects and similar AUC to subjects with two known nonfunctional alleles (15726636). CYP2D6*31 was described in another subject demonstrating decreased dextromethorphan metabolism based on urine metabolites (20473659). Multiple in vitro studies found CYP2D6*31 had nondetectable or markedly decreased enzyme activity compared to wildtype with various substrates (15726636, 24647041, 30366777). CYP2D6*31 is defined by three amino acid substitutions and an analysis of the crystal structure and docking study suggested the Arg440His substitution causes reduced reductase binding resulting in impaired enzyme activity (15726636). Therefore, consensus among experts was no function with an activity value of 0 based on moderate evidence.	{"Latino": 0.007475, "American": 0.006, "European": 0.001476514, "Oceanian": 0.0, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778037	380	CYP2D6	*52	\N	Decreased function	\N	0.25	778036	{24647041,19364831,23897164,30366777}	Limited	\N	CYP2D6*52 is assigned decreased function with an activity value of 0.25 based on limited evidence. Studies found CYP2D6*52 demonstrated decreased enzyme activity compared to wildtype with tamoxifen, bufuralol, dextromethorphan, and primaquine substrates (19364831, 23897164, 24647041, 30366777). This allele has 100C>T (the *10 SNP), 3854G>A (E410K) which we believe does not change function and 4181G>C (*2 SNP) which we also believe is benign. Therefore, consensus among experts was decreased function with limited evidence.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0016893354, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0012988754, "African American/Afro-Caribbean": 0.0}	f
778079	380	CYP2D6	*75	\N	Uncertain function	\N	n/a	778078	{24647041,26652007,30366777}	Inadequate	\N	CYP2D6*75 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*75 demonstrated decreased enzyme activity compared to wildtype with various substrates (26652007, 24647041, 30366777). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00029222333, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778121	380	CYP2D6	*101	\N	No function	\N	0.0	778120	{23394389}	Limited	\N	CYP2D6*101 is assigned no function based on limited evidence. CYP2D6*101 has been described in a subject with CYP2D6*2/*101 genotype demonstrating markedly decreased dextromethorphan metabolism compared to wildtype (23394389). CYP2D6*101 is defined by the same SNPs as CYP2D6*10 in addition to a 19 base pair deletion resulting in a frameshift yielding a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.003, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778159	380	CYP2D6	*120	\N	No function	\N	0.0	778158	{}	Limited	\N	CYP2D6*120 is assigned no function based on limited evidence. CYP2D6*120 is defined by an early stop codon yielding a truncated and nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6481223	30	NAT2	*33	Slow	Decreased function	\N	\N	6481222	{19164093,19909761,15564878}	Moderate	\N	NAT2*33 is assigned decreased function based on moderate evidence. NAT2*33 is characterized by the core SNVs c.341T>C (p.I114T, defining NAT2*5) and c.472A>C (p.I158L). Published in silico modeling predicts that c.472A>C (p.I158L) does not alter NAT2 protein function (19164093, 19909761). Similarly, ten out of ten variant effect predictors tested by CPIC staff predict that c.472A>C (p.I158L) is neutral/tolerated for NAT2 function. Thus, NAT2*33 is assigned decreased function based on c.341T>C (p.I114T) . c.341T>C (p.I114T) defines NAT2*5 which has repeatedly shown decreased NAT2 function in numerous in vivo and in vitro studies. Additionally, an in vitro study showed that NAT2*5 is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*33 would presumably be degraded in the same manner. Five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. While.472A>C is not predicted to impair protein function, it remains unknown whether there are any combinatorial effects associated with c.341T>C and c.472A>C.	\N	f
7096551	16	NAT2	*69	Slow	Decreased function	\N	\N	7096550	{19164093,29273096}	Moderate	\N	NAT2*69 is assigned decreased function based on moderate evidence. NAT2*69 is characterized by the core SNVs c.341T>C (p.I114T) and c.589C>T (p.R197X). c.589C>T results in the amino acid change p.R197X, introducing a premature stop codon leading to the expression of a truncated protein product that is predicted to be nonfunctional (19164093, 29273096). Four out of four variant effect predictors tested by CPIC staff predict that c.589C>T (p.R197X) impairs function. c.341T>C (p.I114T) defines NAT2*5 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. In vitro studies also show that NAT2*5 (which contains the core SNV c.341T>C, p.I114T) is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*69 would presumably be degraded in the same manner. Additionally, five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. NAT2*69 is assigned decreased function based on c.341T>C. Despite this, the combinatorial effects associated with c.341T>C and c.589C>T are uncertain.	\N	f
779071	364	NUDT15	*4	Decreased function	No function	\N	\N	779070	{26878724,28088792,28903549,32094176,36858569,39688234,33753169}	Strong	23.6 Vmax/Km	NUDT15*4 is assigned no function based on strong evidence. Clinical studies have found that NUDT15*1/*4 or NUDT15*2/*4 patients are started on lower doses of thiopurines and exhibit a greater incidence of leukopenia and therapy interruption compared to NUDT15*1/*1 patients (28903549, 36858569). Retrospective analysis found that NUDT15*1/*4 patients tolerated lower thiopurine doses (26878724, 39688234) and exhibited increased levels of dose-normalized DNA-TG in leukocytes compared to NUDT15*1/*1, *1/*2, and *1/*3 patients (39688234). In vitro evidence shows that NUDT15.4 exhibits decreased enzymatic activity (26878724, 33753169), decreased protein expression (32094176) and decreased thermostability (26878724, 28088792, 33753169) compared to NUDT15.1. Published structural modeling indicates that the functional SNV (c.416G>A (p.R139H)) disrupts the α-helix loop and the base of the substrate binding pocket (28088792). These structural destabilizing effects were confirmed using an experimentally derived crystal structure of NUDT15.4 (33753169). Five out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*4-defining SNV, c.416G>A (p.R139H), impairs protein function .	{"Latino": 0.01786, "European": 0.00003285361, "East Asian": 0.0011128682, "Central/South Asian": 0.00003269}	f
779097	142	NUDT15	*17	\N	No function	\N	\N	779096	{}	Limited	\N	NUDT15*17 is assigned no function based on limited evidence. The NUDT15*17 SNV (c.352G>T) results in a premature stop codon(p.E118X) within the Nudix hydrolase domain. Additionally, the stop occurs upstream of c.415C>T, a known "no function" variant. Four out of four variant effect predictors tested by CPIC staff predict that the NUDT15*17 -defining SNV (c.352G>T (p.E118X)) impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
779294	363	SLCO1B1	*9	Decreased function	No function	\N	\N	779293	{11477075,12490595,16697742,16513443,33658230,40047317,39644095}	Moderate	\N	SLCO1B1*9 is assigned no function based on moderate evidence. SLCO1B1*9 is defined by c.1463G>C (p.G488A). In vitro studies demonstrate that protein encoded by SLCO1B1*9 exhibits decreased uptake of estrone sulfate, estradiol 17beta-d-glucuronide, rifampin, rosuvastatin, methotrexate, and atrasentan (11477075, 12490595, 16697742, 16513443, 40047317). A large clinical study demonstrated that individuals with the c.1463G>C variant exhibited significantly increased bilirubin levels relative to those without. Additionally, c.1463G>C was significantly associated with statin-induced myotoxicity (40047317) and has been linked to altered oxylipin levels (39644095). Since c.1463G>A is in strong linkage with c.388A>G (p.N130D) in African populations, the association study (40047317) likely included subjects with either the SLCO1B1*9 or *31 allele Nine out of ten variant effect predictors tested by CPIC staff predict that the SLCO1B1*9-defining variant, c.1463G>C (p.G488A), impairs protein function.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778031	380	CYP2D6	*49	\N	Decreased function	\N	0.5	778030	{19158312,18784265,19364831,24647041,30366777}	Limited	\N	CYP2D6*49 is assigned decreased function based on limited evidence. Subjects with CYP2D6 *1/*49 genotypes demonstrated decreased dextromethorphan metabolism compared to wildtype subjects and subjects with CYP2D6 *10/*49 genotype demonstrated decreased dextromethorphan metabolism compared to subjects with CYP2D6 *1/*10 genotype (19364831). Multiple in vitro studies found CYP2D6*49 had decreased enzyme activity compared to wildtype with multiple substrates (18784265, 19158312, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.009911487, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
3685773	175	RYR1	c.10097G>A	Likely Benign	Normal function	\N	n/a	3685772	{33767344}	\N	\N	BS1	{"Latino": 0.002553, "American": null, "European": 0.001661, "East Asian": null, "Near Eastern": 0.001441, "Central/South Asian": 0.0008282, "Sub-Saharan African": 0.0001448}	f
3685837	175	RYR1	c.12149C>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685836	{35849058}	\N	\N	PS4_Mod, PP1_St, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685885	175	RYR1	c.13918A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685884	{33767344}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779235	363	RYR1	c.14477C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779234	{33767344}	\N	\N	PS3, PS4, PM1_Sup, PP1_St, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779241	363	RYR1	c.14545G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779240	{33767344}	\N	\N	PS3_Mod, PS4, PM1_Sup, PP1_St	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002414}	f
3685777	175	RYR1	c.10229C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685776	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779304	363	SLCO1B1	*14	Increased function	Increased function	\N	\N	779303	{11477075,22147369,23311897,24122874,18781850,24420746,31777781,20139798,32961594}	Strong	\N	SLCO1B1*14 is assigned increased function based on strong evidence in heterozygous and homozygous patients. The lipid-lowering response to fluvastatin is associated with the *14 allele, with greater response in the *14/*14 patients (18781850). The clearance of high-dose methotrexate is significantly faster in patients with two *14 alleles (22147369), and response to low-dose methotrexate is reduced in patients with arthritis (31777781). Exposure to atorvastatin is decreased in heterozygous and homozygous subjects (23311897). The plasma levels of highly sensitive OATP1B1 endogenous substrate GCDCA-3G are significantly lower in *14 carriers than in individuals with the SLCO1B1*1/*1 diplotype (32961594). The *14 allele is associated with increased expression of the transporter in the liver (23311897, 24122874). In vitro studies that normalize the drug uptake to the protein concentration find no increased uptake of rifampin, estrone sulfate, or estradiol 17beta-glucuronide (11477075) and one found decreased uptake of estrone sulfate and ceravistatin (23652407). Therefore, consensus among experts was increased function.	{"American": null, "European": 0.135571, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
779316	362	SLCO1B1	*20	Increased function	Increased function	\N	\N	779315	{15226675,22147369,23311897,32961594}	Limited	\N	SLCO1B1*20 is assigned increased function based on limited in vitro evidence and limited clinical data. Small clinical studies of pravastatin and atorvastatin showed similar pharmacokinetic parameters to subjects with wildtype alleles (15226675, 23311897). One clinical study found significantly increased methotrexate clearance (22147369). The plasma levels of highly sensitive OATP1B1 endogenous substrate GCDCA-3G are significantly lower in *14 carriers than in individuals with the SLCO1B1*1/*1 diplotype (32961594). Therefore, consensus among experts was increased function due to inadequate evidence.	{"American": null, "European": 0.037392758, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779330	362	SLCO1B1	*27	\N	Uncertain function	\N	\N	779329	{22147369,33658230}	Inadequate	\N	SLCO1B1*27 is assigned uncertain function based on limited in vitro evidence and clinical data. One clinical study showed no statistical difference in methotrexate clearance (22147369) and one in vitro study found normal protein expression (33658230). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779393	362	TPMT	*1	\N	Normal function	\N	\N	779392	{8561894,9177237,13679074,16220112,18708949,9246020,15226673,23252716,31005613,23585236,29387964,33928426,27564568,11304783,10580024,19057372}	Definitive	\N	TPMT*1 is assigned normal function based on definitive evidence. TPMT*1 corresponds to the reference sequence, NG_008807.2, containing no SNVs. As such, TPMT.1 activity is used as the reference for in vitro studies using yeast and mammalian cell expression systems (8561894, 9177237, 13679074, 16220112, 18708949). Erythrocytes from individuals genotyped TPMT*1/*1 exhibited normal to high enzymatic activity (9246020, 15226673, 23252716, 31005613). Lastly, TPMT*1/*1 patients have been shown to tolerate standard thiopurine dosing (23585236, 29387964, 33928426, 27564568, 11304783, 10580024, 19057372).	{"Latino": 0.94345534, "European": 0.9534313, "East Asian": 0.979625, "Near Eastern": 0.96561086, "Central/South Asian": 0.9813701, "Sub-Saharan African": 0.9214915, "African American/Afro-Caribbean": 0.92341334}	t
777431	384	CYP2B6	*5	Normal function	Normal function	\N	\N	777430	{11470993,12642465,17559344,20662624,20841522,21659470,22354160,23254426,23399569,23990572,25897175,26389554,26655325,31324697,32238417}	Strong	\N	CYP2B6*5 (c.1459C>T, p.R487C) - Normal function: CYP2B6*5 is assigned normal function based on in vivo (heterozygous and homozygous patients) and in vitro studies. Multiple studies evaluating efavirenz plasma concentrations among patients with HIV found that carriers of the CYP2B6*5 allele had similar efavirenz plasma concentrations compared to the *1 reference (20662624, 20841522, 22354160, 23254426, 23399569, 23990572). A study evaluating efavirenz content in hair samples among HIV patients taking efavirenz for more than three months found that the CYP2B6*5 allele did not impact long term efavirenz exposure (26655325). In human liver microsomes, decreased protein expression and/or activity was reported (11470993, 17559344). In in vitro expression systems, activity ranged from decreased (32238417, 31324697) to no change (21659470) and increased (12642465, 25897175) activity compared to the *1 reference with various substrates. Since differences in protein expression and enzyme activity observed in vitro were not reflected by meaningful differences in vivo in numerous clinical studies (20662624, 20841522, 22354160, 23254426, 23399569, 23990572, 26389554), consensus among experts was normal function based on strong evidence.	{"Latino": 0.038105432, "European": 0.11547839, "Oceanian": 0.02, "East Asian": 0.011, "Near Eastern": 0.024, "Central/South Asian": null, "Sub-Saharan African": 0.02, "African American/Afro-Caribbean": 0.062061857}	f
778777	336	G6PD	Mahidol	III/Deficient	III/Deficient	\N	\N	778776	{22293322,2503817}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.00007218132, "Central/South Asian": 0.000366934, "African American/Afro-Caribbean": 0.0}	f
2677040	121	CYP2D6	*164	\N	\N	\N	\N	2677039	\N	\N	\N	\N	\N	f
778809	336	G6PD	Nilgiri	II/Deficient	II/Deficient	\N	\N	778808	{22293322,18043863}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779338	363	SLCO1B1	*31	Decreased function	No function	\N	\N	779337	{22147369,39511784}	Moderate	\N	SLCO1B1*31 is assigned no function based on moderate evidence. SLCO1B1*31 is defined by c.388A>G (p.N130D, defining *37) and c.1463G>C (p.G488A, defining *9). SLCO1B1*37 is assigned normal function based on strong evidence as c.388A>G was not associated with altered clearance of SLCO1B1-transported drugs. SLCO1B1*9 is assigned no function based on moderate in vitro and clinical evidence. An individual genotyped SLCO1B1*1/*31 exhibited markedly decreased high-dose methotrexate clearance compared to the reference allele, and clearance was decreased compared to a SLCO1B1*5/*5 patient (22147369). An individual genotyped SLCO1B1*31/*41 exhibited an elevated plasma concentration of coproporphyrin I, at a level comparable to SLCO1B1*15/*15 patients, and this individual experienced statin-induced rhabdomyolysis (39511784). In vitro uptake of methotrexate by protein encoded by SLCO1B1*31 was significantly decreased compared to the reference; transport activity was similar to empty vector controls (22147369). Ten out of ten variant effect predictors (VEPs) tested by CPIC staff predict that c.388A>G is neutral for protein function. Nine out of ten VEPs predict that c.1463G>C impairs protein function.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777483	384	CYP2B6	*32	Normal function	Normal function	\N	\N	777482	{26655325,30201214}	Limited	\N	CYP2B6*32 (c.1219G>A, p.A407T) – Normal function: CYP2B6*32 is assigned normal function. A study evaluating efavirenz content in hair samples among patients with HIV taking efavirenz for more than three months found CYP2B6*32 did not impact long term efavirenz content (26655325) compared to the *1 reference. Although one in vitro study using a cDNA expression system found that CYP2B6*32 demonstrated increased enzyme activity compared to the *1 reference (30201214), the experts did not find these results convincing. Therefore, consensus among experts was normal function based on limited evidence.	{"Latino": 0.00002978, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
2677052	121	CYP2D6	*170	\N	\N	\N	\N	2677051	\N	\N	\N	\N	\N	f
2677042	121	CYP2D6	*165	\N	\N	\N	\N	2677041	\N	\N	\N	\N	\N	f
778783	336	G6PD	Toledo	II/Deficient	II/Deficient	\N	\N	778782	{22293322,22139979}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779397	362	TPMT	*3A	\N	No function	\N	\N	779396	{16220112,9177237,9103127,18708949,8644731,8561894,15967990,9246020,9931346,15226673,23252716,31005613,11304783,10580024,19057372,33205673,23585236,29387964,33928426}	Definitive	\N	TPMT*3A is assigned no function based on definitive evidence. Erythrocytes from individuals heterozygous for TPMT*3A exhibited intermediate enzymatic activity, while erythrocytes from individuals homozygous for TPMT*3A or heterozygous for TPMT*3A in combination with another no function allele exhibited low enzymatic activity (9103127, 9246020, 9931346, 15226673, 23252716, 31005613). Patients carrying TPMT*3A alleles exhibited increased plasma concentrations of TGNs, decreased plasma concentrations of methylated metabolites, and tolerate lower doses of thiopurines (10580024, 11304783, 19057372, 23585236, 29387964, 33205673, 33928426). In vitro studies found that TPMT.3A protein expression and enzymatic activity is substantially decreased or undetectable relative to TPMT.1 in yeast cells (8644731, 9177237), mammalian cells (16220112,18708949, 8561894), and patient erythrocytes (9177237, 8644731, 8561894). Loss of TPMT.3A protein expression is attributed to rapid degradation by the proteasome (16220112, 9177237, 15967990). Seven and eight out of ten variant effect predictors tested by CPIC staff predict that the TPMT*3A-defining SNVs, c.460G>A (p.A154T) and c.719A>G (p.Y240C), impair protein function, respectively.	{"Latino": 0.041727107, "European": 0.033840433, "East Asian": 0.00030599828, "Near Eastern": 0.0130693065, "Central/South Asian": 0.0042245653, "Sub-Saharan African": 0.0016235898, "African American/Afro-Caribbean": 0.008}	f
2899143	173	CYP2B6	*39	Decreased function	Decreased function	\N	\N	2899142	{14551287,18171905,24260284,38596098}	Limited	\N	CYP2B6*39 (c.418C>T, p.R140W; c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R) – Decreased function: CYP2B6*39 is assigned decreased function. CYP2B6*39 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information). As is the same for *6, the mechanism for decreased activity is aberrant splicing caused by c.516G>T, which leads to reduced amounts of protein and thus, activity (14551287, 18171905, 24260284). As a result, alleles having c.516G>T are considered decreased function, regardless of the functional status of additional other variants unless these cause no function (e.g., CYP2B6*13 and CYP2B6*38). A single in vitro study reported decreased function for p.R140W using buproprion and efavirez as probes (38596098). Therefore, the consensus among experts was decreased function based on the presence of c.516G>T and limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777967	380	CYP2D6	*17	\N	Decreased function	\N	0.5	777966	{8764380,8971426,9415713,11823760,24647041,30366777}	Moderate	\N	CYP2D6*17 is assigned decreased function based on moderate evidence. CYP2D6*17 has consistently been described in heterozygous and homozygous subjects demonstrating decreased metabolism of various CYP2D6 substrates compared to wildtype subjects based on urine metabolites (8764380, 8971426, 11823760). Multiple in vitro studies found CYP2D6*17 had at least modestly decreased enzyme activity compared to wildtype with various substrates (9415713, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on moderate evidence.	{"Latino": 0.023261126, "American": 0.0052698795, "European": 0.0039216722, "Oceanian": 0.0010413943, "East Asian": 0.00009343609, "Near Eastern": 0.030970177, "Central/South Asian": 0.0004806022, "Sub-Saharan African": 0.19355686, "African American/Afro-Caribbean": 0.16882424}	f
779009	336	G6PD	Bangkok Noi	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	779008	{22293322,21302115}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
6481239	30	NAT2	*41	\N	Uncertain function	\N	\N	6481238	{19909761}	Inadequate	\N	NAT2*41 is assigned uncertain function based on inadequate evidence. NAT2*41 is characterized by the core SNV c.578C>T (p.T193M). Published in silico modeling predicts that c.578C>T (p.T193M) impairs protein function based on exposure of hydrophobic residues that may facilitate protein aggregation or targeted degradation (19909761). Similarly, six out of ten variant effect predictors tested by CPIC staff predict that c.578C>T (p.T193M) impairs protein function. There are no in vitro or in vivo functional studies for NAT2*41	\N	f
6481247	30	NAT2	*45	\N	Uncertain function	\N	\N	6481246	{19909761,24444407}	Inadequate	\N	NAT2*45 is assigned uncertain function based on inadequate evidence. NAT2*45 is characterized by the core SNV c.29T>C (p.I10T). Published in silico modeling predicts that c.29T>C (p.I10T) does not alter NAT2 protein function (19909761). Five out of ten variant effect predictors tested by CPIC staff predict that c.29T>C (p.I10T) impairs NAT2 protein function. Additionally, a structure-based computational prediction tool predicts that c.29T>C (p.I10T) decreases NAT2 protein stability which could lead to decreased function. The limited clinical data available for NAT2*45 was not sufficient to influence the allele clinical functional status (24444407).	\N	f
777429	384	CYP2B6	*4	Increased function	Increased function	\N	\N	777428	{12642465,14515060,17015050,17235330,21659470,21746968,21821736,21976622,23254426,23399569,25934575,26389554,29637923,30085944,30906561,31324697,32238417,35538637}	Moderate	\N	CYP2B6*4 (c.785A>G, p.K262R) - Increased function: CYB2B6*4 is assigned increased function based on in vivo (heterozygous patients only) and in vitro studies. In clinical studies, CYP2B6*4 heterozygotes had significantly increased metabolism of several substrates such as bupropion (14515060, 29637923), nicotine (17015050) and efavirenz (17235330). Numerically higher methadone clearance was observed in CYP2B6*4 carriers, albeit samples sizes were small (26389554, 35538637). Although two studies did not find increased efavirenz clearance compared to the *1 reference (23399569, 23254426), the experts did not find these results convincing due to the small sample size. Multiple in vitro studies using cDNA expression systems showed that CYP2B6*4 has increased activity compared to the *1 reference towards efavirenz, methadone, bupropion nicotine, artemether and selegiline, (12642465, 21746968, 21821736, 31324697, 32238417). One in vitro study using cDNA expression system showed no difference in activity using bupropion as a probe (21659470), but the experts did not find this evidence convincing. Some studies found CYP2B6*4 had less activity compared to the *1 reference towards ketamine, nicotine, cyclophosphamide and ifosphamide (21821736, 21976622, 25934575, 30085944, 30906561). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was increased function based on moderate evidence, but effects may be substrate-dependent.	{"Latino": 0.10623067, "European": 0.040871028, "Oceanian": 0.0, "East Asian": 0.0841915, "Near Eastern": 0.104, "Central/South Asian": 0.099, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.010298969}	f
2677044	121	CYP2D6	*166	\N	\N	\N	\N	2677043	\N	\N	\N	\N	\N	f
777993	380	CYP2D6	*30	\N	Uncertain function	\N	n/a	777992	{24647041,30366777}	Inadequate	\N	CYP2D6*30 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*30 demonstrated decreased enzyme activity compared to wildtype with tamoxifen, bufuralol, dextromethorphan, and primaquine substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse and not consistent among substrates. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": 0.0, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
779413	362	TPMT	*9	\N	Uncertain function	\N	\N	779412	{15226673,16220112,18602085,18708949,23252716,30840585,31005613}	Inadequate	\N	TPMT*9 is assigned uncertain function based on inadequate evidence. Clinically, erythrocytes from individuals genotyped TPMT*1/*9 exhibited intermediate activity (15226673, 18602085, 23252716, 30840585, 31005613). However, one individual genotyped TPMT*1/*9 exhibited normal TPMT enzymatic activity (15226673). An individual genotyped TPMT*1/*9 received 67 mg/m2 6-MP and exhibited a 6-TGN concentration of 502 pmol, which is above the therapeutic range (23252716). In vitro studies using mammalian expression systems found that TPMT.9 protein expression is comparable to TPMT.1 (16220112, 18708949). However, one study found that TPMT.9 exhibited normal enzymatic activity at ~92% of TPMT.1 activity using 6-MP as a substrate (16220112), while another found that enzymatic activity was decreased by 25% using 6-TG as a substrate (18708949). Similarly, TPMT.9 expressed in yeast cells exhibited a 25% decrease in enzymatic activity compared to TPMT.1, as well as decreased affinity for 6-TG (18602085). Molecular modeling suggests that TPMT.9 exhibited decreased protein stability (18602085). Five out of ten variant effect predictors tested by CPIC staff predict that the TPMT*9-defining SNV, c.356A>C (p.K119T), impairs protein function.	{"Latino": 0.0001163, "European": 0.0005553769, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
779423	362	TPMT	*14	\N	No function	\N	\N	779422	{18708949,15083071,31005613}	Moderate	\N	TPMT*14 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*3A/*14 and TPMT*1/*14 exhibited very low and intermediate enzymatic activity, respectively (15083071, 31005613). An in vitro study using a mammalian cell expression system found that TPMT.14 protein expression and enzymatic activity are undetectable in cells (18708949). Four out of eight variant effect predictors tested by CPIC staff predict that the TPMT*14-defining SNV, c.1A>G (p.M1V), impairs protein function. c.1A>G (p.M1V) is predicted to disrupt protein translation due to the loss of the canonical start codon, and there is no alternative start codon available	{"Latino": null, "European": 0.0, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
779437	362	TPMT	*21	\N	No function	\N	\N	779436	{18708949,18602085,16917910,23252716,33118454}	Moderate	\N	TPMT*21 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*1/*21 exhibited intermediate activity (18602085, 16917910, 23252716). Additionally, a patient genotyped TPMT*1/*21 was prescribed 41 mg/m2 thioguanine and exhibited a plasma TGN concentration of 4060 pmol, which is above the therapeutic range (23252716). Erythrocytes from an individual genotyped TPMT*3A/*21 had undetectable enzymatic activity (33118454). An in vitro study using a mammalian cell expression system found that TPMT.21 enzymatic activity was undetectable (18708949). An additional in vitro study using a yeast expression system found that TPMT.21 enzymatic activity is decreased by 75% compared to TPMT.1 and molecular modeling suggests that TPMT.21 alters the co-factor binding site (18602085). Seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*21-defining SNV, c.205C>G (p.L69V), impairs protein function.	{"Latino": 0.0, "European": 0.00005822823, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
6481197	30	NAT2	*6	Slow	Decreased function	\N	\N	6481196	{9154882,8781741,29589062,28653770,8102597,30564082,15558239,7668286,2376572,1451720,10744128,22092036,1872889,20040334,9333101,22970273,16531626,15565348,9321764,9110365,11214777,31257615,24702251,24444407,15110095,27509179,11773863,20801937,21750470,23899363,9565293,9891107,9682266,24221535,22105431,8287065,27223070,8001235,8923605,10762005,8081359,35928262,28752039,17505821,21946899,16570187,15032315,18167504,17434923,33815485,18680467,19336229,7669073,11337936,28516247}	Definitive	\N	NAT2*6 is assigned decreased function based on definitive evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*6 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*6 is characterized by the core SNVs c.590G>A (p.R197Q) and c.803G>A (p.R268K). c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. The functional SNV c.590G>A (p.R197Q) has been studied for more than 25 years and has shown decreased N-acetylation activity in numerous clinical and in vitro studies using various substrates. Clinical studies have demonstrated that individuals homozygous for NAT2*6 or heterozygous for NAT2*6 in combination with another decreased function allele exhibit decreased acetylation activity toward caffeine metabolites (8102597, 7668286, 9891107, 10744128, 20801937, 22970273, 24221535, 28653770), isoniazid (2376572, 9154882, 9321764, 19336229, 35928262), sulphonamides (1872889, 15032315, 16570187, 18167504, 21946899), and dapsone (10762005). Individuals homozygous for NAT2*6 or heterozygous for NAT2*6 in combination with another decreased function allele exhibit increased hydralazine exposure (24702251, 31257615). Seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. In vitro studies have shown that NAT2*6 exhibits decreased thermostability and decreased protein expression (11337936, 17434923, 8081359) as well as decreased acetylation toward various substrates (7669073, 33815485). Several studies indicate the existence of an ultra-slow acetylator phenotype in individuals homozygous for the NAT2*6 allele compared with other NAT2 decreased function alleles (29018032, 28653770, 24221535, 33815485, 7668286, 22970273, 28752039, 16570187, 28516247).	\N	f
777453	384	CYP2B6	*17	Normal function	Normal function	\N	\N	777452	{16272958,26655325,30201214,32238417,35538637}	Limited	\N	CYP2B6*17 (c.76A>T, p.T26S; c.83A>G, p.D28G; c.85C>A+c.86G>C, p.R29T) – Normal function: CYP2B6*17 is assigned normal function. A study evaluating efavirenz content in hair samples among HIV patients taking efavirenz for more than three months found that long term efavirenz exposure was not impacted by the CYP2B6*17 allele (26655325). Additionally, CYP2B6*17 had similar enzyme activity in vitro using cDNA expression systems compared to the *1 reference (16272958, 30201214, 32238417), but decreased activity for methadone (35538637). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was normal function based on limited evidence.	{"Latino": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0126, "African American/Afro-Caribbean": 0.071}	f
2677046	121	CYP2D6	*167	\N	\N	\N	\N	2677045	\N	\N	\N	\N	\N	f
778049	379	CYP2D6	*58	\N	Unknown function	\N	n/a	778048	{}	No Evidence	\N	CYP2D6*58 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0012297297}	f
778075	379	CYP2D6	*73	\N	Unknown function	\N	n/a	778074	{}	No Evidence	\N	CYP2D6*73 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0022734273, "African American/Afro-Caribbean": 0.0}	f
2677048	121	CYP2D6	*168	\N	\N	\N	\N	2677047	\N	\N	\N	\N	\N	f
2677050	121	CYP2D6	*169	\N	\N	\N	\N	2677049	\N	\N	\N	\N	\N	f
6481267	30	NAT2	*55	\N	Unknown function	\N	\N	6481266	{}	No evidence	\N	NAT2*55 is assigned unknown function based on a lack of evidence. NAT2*55 is characterized by the core SNVs c.51C>G (p.N17K) and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.51C>G (p.N17K). Ten out of ten variant effect predictors tested by CPIC staff predict that c.51C>G (p.N17K) is neutral for protein function.	\N	f
777581	384	CYP2C19	*28	\N	Normal function	\N	\N	777580	{25001882,20712527}	Limited	\N	CYP2C19*28 is assigned normal function based on limited in vitro and computational evidence. An in vitro study found CYP2C19*28 had similar intrinsic clearance compared to wildtype with a mephenytoin substrate (25001882). A computational analysis including splice site, mFold and nonsynonymous mutation analysis, did not find a deleterious impact on enzyme function (20712527). Although CYP2C19*28 was found to have increased intrinsic clearance compared to wildtype with a clopidogrel substrate in vitro (25001882), the experts did not find this result convincing as computational analysis and in vitro data with mephenytoin did not support increased function. Therefore, consensus among experts was normal function based on limited evidence as it was determined the phenotypes containing this allele would be clinically similar to phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0037037036, "African American/Afro-Caribbean": null}	f
778125	379	CYP2D6	*103	\N	Unknown function	\N	n/a	778124	{}	No Evidence	\N	CYP2D6*103 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0033, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3318540	95	CYP2D6	*172	\N	\N	\N	\N	3318539	\N	\N	\N	\N	\N	f
5175553	42	CYP2D6	*174	\N	\N	\N	\N	5175552	\N	\N	\N	\N	\N	f
5175555	42	CYP2D6	*175	\N	\N	\N	\N	5175554	\N	\N	\N	\N	\N	f
5763833	32	CYP2D6	*177	\N	\N	\N	\N	5763832	\N	\N	\N	\N	\N	f
6481273	30	NAT2	*58	Slow	Decreased function	\N	\N	6481272	{29273096}	Moderate	\N	NAT2*58 is assigned decreased function based on moderate evidence. NAT2*58 is characterized by the core SNVs c.346G>A (p.G116S), c.590G>A (p.R197Q) and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no experimental evidence describing function for c.346G>A (p.G116S). Five out of ten variant effect predictors tested by CPIC staff predict that c.346G>A (p.G116S) impairs protein function, which is supported by published in silico analysis (29273096). c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. Thus, NAT2*58 is assigned decreased function based on c.590G>A. Despite this, the combinatorial effects associated with c.346G>A and c.590G>A are uncertain	\N	f
778167	380	CYP2D6	*124	\N	No function	\N	0.0	778166	{}	Limited	\N	CYP2D6*124 is assigned no function based on limited evidence. CYP2D6*124 is defined by a deletion resulting in a frameshift and yielding a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6481285	30	NAT2	*64	Slow	Decreased function	\N	\N	6481284	{}	Moderate	\N	NAT2*64 is assigned decreased function based on moderate evidence. NAT2*64 is characterized by the core SNVs c.590G>A (p.R197Q), c.796G>A (p.V266M) and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.796G>A (p.V266M). Three out of ten variant effect predictors tested by CPIC staff predict c.796G>A (p.V266M) impairs protein function. c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. Thus, NAT2*64 is assigned decreased function based on c.590G>A. Despite this, the combinatorial effects associated with c.796G>A and c.590G>A are uncertain	\N	f
777783	384	CYP2C9	*58	Decreased function	Uncertain function	\N	n/a	777782	{25142737,25075423,25884291}	Inadequate evidence	\N	CYP2C9*58 is assigned uncertain function due to inadequate evidence. CYP2C9*58 was first described in a patient requiring a low weekly warfarin dose of 9mg (25075423). No variant was observed in VKORC1 or CYP4F2 in this patient and a subsequent in silico study showed changes in hydrogen bonding which may affect the secondary structure of the protein. In vitro studies found CYP2C9*58 demonstrated decreased enzyme activity with multiple substrates (25142737, 25075423, 25884291). Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778165	379	CYP2D6	*123	\N	Uncertain function	\N	n/a	778164	{31368850}	Inadequate	\N	CYP2D6*123 is assigned uncertain function due to inadequate data describing function of this allele. *123 has the same core SNPs as *41 plus 2870T>C (L302P); this is the only allele with the latter and there does not seem to be additional functional information. Therefore, consensus among experts was uncertain function due to no available evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1406318	366	CYP2C9	*73	Unknown function	Unknown function	\N	n/a	1406317	{}	No evidence	\N	CYP2C9*73 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": 0.0, "American": null, "European": 0.00010, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.00040, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778205	286	CYP2D6	*143	\N	No function	\N	0.0	778204	{33998274}	Limited	\N	CYP2D6*143 is assigned no function based on limited evidence. CYP2D6*143 is defined by a premature stop codon predicted to yield truncated protein and thus be nonfunctional. A subject sequenced as CYP2D6*143/*144 had a risperidone/9-hydroxy-risperidone ratio that was higher (indicating lower activity) compared to that found in subjects with two no function alleles(33998274). Therefore, consensus among experts was no function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777733	384	CYP2C9	*33	Decreased function	No function	\N	0.0	777732	{23752738,18971529,23844998,24118918,25142737,25951663,25144335,25476996,25832633,25884291,27163851,19541829,24077631}	Limited	\N	CYP2C9*33 is assigned no function based on limited evidence. Multiple in vitro studies using different cell systems found CYP2C9*33 demonstrated decreased clearance for numerous substrates compared to wildtype and similar clearance compared to CYP2C9*3 which definitively has no function (23752738, 18971529, 23844998, 24118918, 25142737, 25951663, 25144335, 25476996, 25832633, 25884291, 27163851, 19541829, 24077631). Although one patient with CYP2C9 *1/*33 genotype had their blood pressure lowered with losartan, the experts did not find this result convincing due to the small sample size (18971529). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00065227173, "Near Eastern": 0.001, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777787	384	CYP2C9	*60	Decreased function	Uncertain function	\N	n/a	777786	{25142737,26255664,25884291}	Inadequate evidence	\N	CYP2C9*60 is assigned uncertain function due to inadequate evidence. CYP2C9*60 was first described in a patient requiring a low daily warfarin dose of 1.5mg (26255664). In vitro studies found CYP2C9*60 demonstrated enzyme activity ranging from decreased to similar activity compared to wildtype with various substrates (25142737, 26255664, 25884291). Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777753	384	CYP2C9	*43	No function	No function	\N	0.0	777752	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25951663,27163851,23844998}	Limited	\N	CYP2C9*43 is assigned no function based on limited evidence in in vitro studies. Multiple in vitro studies found CYP2C9*43 demonstrated markedly decreased clearance compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25951663, 27163851, 23844998). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function or decreased function alleles.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.00010, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777755	384	CYP2C9	*44	Decreased function	Decreased function	\N	0.5	777754	{24077631,24118918,25142737,25144335,25476996,25832633,25951663,25884291,25924705,27163851,23844998}	Limited	\N	CYP2C9*44 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*44 demonstrated decreased clearance compared to wildtype (24118918, 25476996, 25144335, 25832633, 25951663, 25884291, 25924705, 23844998, 24077631). Although two in vitro studies showed CYP2C9*44 had similar activity compared to wildtype, the experts did not find these results convincing as in these studies CYP2C9*2 which definitively has decreased function, demonstrated increased or similar activity compared to wildtype in these studies (25142737, 27163851). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.00030, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777961	380	CYP2D6	*13	\N	No function	\N	0.0	777960	{8554938}	Limited	\N	CYP2D6*13 is assigned no function based on limited evidence. CYP2D6*13 was first described in a subject demonstrating markedly decreased dextromethorphan metabolism (8554938). CYP2D6*13 is a CYP2D7-CYP2D6 hybrid allele resulting in a premature stop codon and yielding a truncated nonfunctional enzyme. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": 0.001, "European": 0.00091628334, "Oceanian": null, "East Asian": 0.0012615201, "Near Eastern": null, "Central/South Asian": 0.00074228394, "Sub-Saharan African": 0.001, "African American/Afro-Caribbean": 0.000562724}	f
3685725	175	RYR1	c.8360C>G	Benign	Normal function	\N	n/a	3685724	{35849058}	\N	\N	BA1	{"Latino": 0.002814, "American": null, "European": 0.0004409, "East Asian": null, "Near Eastern": 0.01152, "Central/South Asian": 0.0004144, "Sub-Saharan African": 0.02895}	f
3685731	175	RYR1	c.8600T>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685730	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685781	175	RYR1	c.10252A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685780	{35849058}	\N	\N	PS4_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685877	175	RYR1	c.13672C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685876	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685963	175	RYR1	c.14803G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685962	{35849058}	\N	\N	PS4_Mod, PM1_Sup, PP1_St, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778057	380	CYP2D6	*62	\N	No function	\N	0.0	778056	{17460029,24647041,30366777}	Limited	\N	CYP2D6*62 is assigned no function based on limited evidence. CYP2D6*62 has been described in a subject with reduced enzyme activity with a sparteine substrate (17460029). Multiple in vitro studies found CYP2D6*62 had nondetectable enzyme activity with multiple substrates (17460029, 24647041, 30366777). CYP2D6*62 is defined by a SNP which disrupts heme incorporation resulting in a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685619	175	RYR1	c.7084G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685618	{35849058}	\N	\N	PS4_Mod, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685623	175	RYR1	c.7089C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685622	{35849058}	\N	\N	PS4_Mod, PM1	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779213	363	RYR1	c.7354C>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	779212	{33767344}	\N	\N	PS3_Mod, PS4_Mod, PM1, PP1_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685865	175	RYR1	c.12848A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685864	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": 0.000199, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779322	363	SLCO1B1	*23	Decreased function	No function	\N	\N	779321	{22147369}	Limited	\N	SLCO1B1*23 is assigned no function based on limited evidence in heterozygous patients and in vitro studies. A clinical study of 1 heterozygous carrier of *23 showed markedly decreased high-dose methotrexate clearance compared to wildtype, slower than a *5/*5 patient (22147369). In vitro uptake was severely diminished compared to wildtype (22147369). Computational activity predictions support the in vitro and in vivo data (22147369).Therefore, consensus among experts was no function with limited evidence.	{"American": null, "European": 0.00010, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.00010, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1002690	356	SLCO1B1	*39	\N	No function	\N	\N	1002689	{32082363,36964102}	Limited	\N	SLCO1B1*39 is assigned no function based on limited evidence. SLCO1B1*39 is defined by c.388A>G (p.N130D, defining *37) and c.757C>T (p.R253X). The latter results in the generation of a premature stop codon and expression of a truncated protein while c.388A>G is associated with normal SLCO1B1 function. The nonsense variant occurs upstream of the known "no function" variant (c.1463G>C, defining *9 and *31), suggesting that loss of this region of the protein alters function. Additionally, SLCO1B1 loss-of-function has been implicated in the pathogenesis of Rotor syndrome and SLCO1B1*39 has been identified in a homozygous or compound heterozygous state in three cases (32082363, 36964102). Ten out of ten variant effect predictors (VEPs) tested by CPIC staff predict that c.388A>G is neutral for protein function. Four out of four VEPs capable of making predictions for nonsense variants predict that c.757C>T impairs protein function.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777683	384	CYP2C9	*8	Decreased function	Decreased function	\N	0.5	777682	{23752738,22378156,23959274,16220110,21811894,23844998,24118918,25142737,25144335,25476996,25832633,25884291,25924705,27163851,27199745,25951663,24077631,15289788,28758225,23376925,15284535}	Definitive	\N	CYP2C9*8 is assigned decreased function based on definitive evidence in heterozygous patients and in vitro studies. Ten CYP2C9*1/*8 genotype patients on a stable warfarin dose had 28% lower S-warfarin clearance compared to wildtype patients which correlated with the in vitro kinetic study demonstrating the CYP2C9*8 protein had 30% reduced warfarin clearance compared to wildtype (22378156). The CYP2C9*8 allele was associated with decreased phenytoin metabolism in 19 subjects (CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*8/*11, or CYP2C9*5/*8) compared to wildtype subjects based on urinary excretion of a phenytoin metabolite after a single 300mg dose (16220110). Four CYP2C9*1/*8 subjects had decreased diclofenac metabolism compared to wildtype subjects based on the urinary metabolite ratio after a single 50mg dose (23959274). One in vitro study showed CYP2C9*8 had decreased mRNA expression compared to wildtype, resulting in decreased function and metabolism of substrates (23376925). Decreased metabolism of multiple substrates compared to wildtype was demonstrated in a series of in vitro studies (23752738, 27199745, 23844998, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25924705, 27163851, 25951663, 24077631). Although an in vitro study showed similar diclofenac metabolism compared to wildtype (22378156), the experts did not find this conflicting because four CYP2C9*1/*8 subjects exhibited decreased diclofenac metabolism as previously described (23959274). Additionally, the experts did not deem two in vitro studies where CYP2C9*8 demonstrated similar to increased enzyme activity compared to wildtype (28758225, 15284535) as conflicting evidence because both studies used the same system, and it could not be ruled out that these results which differed from the majority of in vitro studies were due to the specific system. Although six CYP2C9*1/*8 subjects had similar acenocoumarol metabolite plasma concentrations compared to wildtype subjects 8 and 24 hours after a single 8mg dose (21811894), the experts did not deem this result as conflicting evidence based on the small sample size. Similarly, two CYP2C9 *1/*8 subjects had a similar urinary losartan-metabolite ratio compared to wildtype after a single 25mg dose and the experts did not deem this result as convincing conflicting evidence based on the small sample size (15289788). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on definitive evidence.	{"Latino": 0.0073706377, "American": 0.020382864, "European": 0.0018053303, "Oceanian": null, "East Asian": 0.0037306643, "Near Eastern": 0.00064213155, "Central/South Asian": 0.0009815951, "Sub-Saharan African": 0.075846866, "African American/Afro-Caribbean": 0.059034664}	f
778043	380	CYP2D6	*55	\N	Decreased function	\N	0.5	778042	{18784265,24647041,30366777}	Limited	\N	CYP2D6*55 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2D6*55 had decreased enzyme activity compared to wildtype with multiple substrates (18784265, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00019958949, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778163	379	CYP2D6	*122	\N	Unknown function	\N	n/a	778162	{}	No Evidence	\N	CYP2D6*122 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.001, "African American/Afro-Caribbean": 0.003}	f
779035	336	G6PD	Buenos Aires	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	779034	{22293322,18086567}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779013	336	G6PD	Canton, Taiwan-Hakka, Gifu-like, Agrigento-like	II/Deficient	II/Deficient	\N	\N	779012	{22293322,2263506,1953767,22963789}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.00003574748, "European": 0.0, "East Asian": 0.010610976, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
779741	314	CYP2D6	*41x3	\N	Decreased function	\N	0.75	778014	{11037799,15289790,17001295,17112815,19364831}	Limited	\N	CYP2D6*41x3 is assigned decreased function based on limited evidence. CYP2D6*41 is assigned decreased function based on decreased protein expression and enzyme activity (11037799, 15289790, 17112815, 19364831, 17001295). Therefore, consensus among experts was decreased function with an activity value of 0.75 based on limited evidence as it was determined the phenotypes containing a duplication of this allele would demonstrate greater protein expression and enzyme activity than that of the nonduplicated allele and be clinically similar to phenotypes comprising decreased function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778941	336	G6PD	Hartford	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778940	{22293322,1945893}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
6481231	30	NAT2	*37	Slow	Decreased function	\N	\N	6481230	{29273096}	Moderate	\N	NAT2*37 is assigned decreased function based on moderate evidence. NAT2*37 is characterized by the core SNVs c.590G>A (p.R197Q), c.638C>T (p.P213L) and c.803G>A. c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no experimental evidence describing function for c.638C>T (p.P213L). Seven out of ten variant effect predictors tested by CPIC staff predict that c.638C>T (p.P213L) impairs protein function, which is supported by published in silico analysis (29273096). c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A impairs protein function. Thus, NAT2*37 is assigned decreased function based on c.590G>A. Despite this, it remains unknown whether there are any combinatorial effects associated with c.638C>T and c.590G>A.	\N	f
778069	380	CYP2D6	*70	\N	Uncertain function	\N	n/a	778068	{24647041,30366777}	Inadequate	\N	CYP2D6*70 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*70 demonstrated decreased enzyme activity compared to wildtype with various substrates (24647041, 30366777) but consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
778161	379	CYP2D6	*121	\N	Unknown function	\N	n/a	778160	{}	No Evidence	\N	CYP2D6*121 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.003}	f
778755	336	G6PD	Mt Sinai	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778754	{22293322,32387609,9452072}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
777969	380	CYP2D6	*18	\N	No function	\N	0.0	777968	{8946471,10471060,18784265,24647041,30366777}	Moderate	\N	CYP2D6*18 is assigned no function based on moderate evidence. CYP2D6*18 is defined by a 9 base insertion yielding a nonfunctional enzyme and has been described in subjects demonstrating markedly decreased metabolism of sparteine and debrisoquine (8946471, 10471060). Multiple in vitro studies found CYP2D6*18 had decreased enzyme activity compared to wildtype with various substrates (8946471, 18784265, 24647041, 30366777). Therefore, consensus among experts was no function with an activity value of 0 based on moderate evidence.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0013486103, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778007	380	CYP2D6	*37	\N	Uncertain function	\N	n/a	778006	{24647041,30366777}	Inadequate	\N	CYP2D6*37 is assigned uncertain function based on inadequate evidence. In vitro studies found CYP2D6*37 demonstrated decreased enzyme activity compared to wildtype with tamoxifen, bufuralol, dextromethorphan, and primaquine substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse and not consistent among substrates. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778033	380	CYP2D6	*50	\N	Decreased function	\N	0.5	778032	{18784265,24647041,30366777}	Limited	\N	CYP2D6*50 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2D6*50 had decreased enzyme activity compared to wildtype with multiple substrates (18784265, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.00039791822, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
778745	336	G6PD	Santa Maria	II/Deficient	II/Deficient	\N	\N	778744	{22293322,7959686,1879833,9250351}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778807	336	G6PD	Santiago	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778806	{22293322,1611091}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
777999	380	CYP2D6	*33	\N	Normal function	\N	1.0	777998	{9241659,24647041,30366777}	Limited	\N	CYP2D6*33 is assigned normal function based on limited evidence. CYP2D6*33 was first described in a subject with CYP2D6 *5/*33 genotype demonstrating similar sparteine metabolism compared to CYP2D6 *1/*5 and CYP2D6 *2/*5 subjects, indicating normal enzyme activity (9241659). In vitro studies similarly found CYP2D6*33 had normal enzyme activity and similar intrinsic clearance compared to wildtype with various substrates (24647041, 30366777). Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence as it was determined the phenotypes containing this allele would be clinically similar to phenotypes comprising normal function alleles.	{"Latino": null, "American": 0.0022216009, "European": 0.009507331, "Oceanian": null, "East Asian": 0.00021425438, "Near Eastern": 0.0, "Central/South Asian": 0.002, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778835	336	G6PD	Wayne	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778834	{22293322,3565372}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685515	175	RYR1	c.5317C>T	Benign	Normal function	\N	n/a	3685514	{33767344}	\N	\N	BA1	{"Latino": null, "American": null, "European": null, "East Asian": 0.01348, "Near Eastern": null, "Central/South Asian": 0.0002069, "Sub-Saharan African": null}	f
3685965	175	RYR1	c.14813T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685964	{35849058}	\N	\N	PS3_Mod, PS4_Sup, PM1_Sup, PP3_Mod, BS2_Mod, BS3_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685973	175	RYR1	c.14825G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685972	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685975	175	RYR1	c.14879T>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685974	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3827889	157	MT-RNR1	m.896A>G	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827888	{18830133}	Inadequate evidence	\N	MT-RNR1 896A>G is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. Screening of individuals with aminoglycoside-hearing loss identified this variant in one study (18830133). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.0030198046, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null}	f
3827909	157	MT-RNR1	m.1243T>C	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827908	{7550368}	Inadequate evidence	\N	MT-RNR1 1243T>C is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. Screening of individuals with aminoglycoside-hearing loss identified this variant in one study (7550368). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.023302607, "East Asian": 0.0006748, "Near Eastern": 0.01625, "Central/South Asian": 0.02612, "Sub-Saharan African": null}	f
778115	380	CYP2D6	*98	\N	Uncertain function	\N	n/a	778114	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*98 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*98 demonstrated enzyme activity ranging from similar to decreased activity compared to wildtype with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). Therefore, consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778179	379	CYP2D6	*130	\N	Uncertain function	\N	n/a	778178	{32759992}	Inadequate	\N	CYP2D6*130 is assigned uncertain function due to inadequate literature describing function of this allele. One in vitro study demonstrated substantially decreased intrinsic clearance CLint (Vmax/Km) of 3.2% compared to *1 for tamoxifen N-desmethylation; no activity was detectable for dextromethorphan O-demethylation (32759992). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778737	336	G6PD	Sao Borja	IV/Normal	IV/Normal	\N	\N	778736	{22293322,8436389}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.000054038475, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778731	336	G6PD	Sierra Leone	III/Deficient	III/Deficient	\N	\N	778730	{22293322,32387609,18452027}	Inadequate	\N	Function assigned based on evidence supporting decreased enzyme activity resulting in a WHO class III assignment (32387609).	{"Latino": 0.000035720663, "European": 0.0025682764, "East Asian": 0.0, "Central/South Asian": 0.00031527507, "African American/Afro-Caribbean": 0.00015804447}	f
778967	336	G6PD	Suwalki	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778966	{22293322,14757424}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779001	336	G6PD	Union,Maewo, Chinese-2, Kalo	II/Deficient	II/Deficient	\N	\N	779000	{22293322,4405605,8447319,1303180,8935319}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.00017860332, "European": 0.000045371227, "East Asian": 0.0006079438, "Central/South Asian": 0.00010502547, "African American/Afro-Caribbean": 0.0004229671}	f
3685429	175	RYR1	c.1565A>G	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685428	{35849058}	\N	\N	PS4_Mod, PM1_Sup, PM5, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685435	175	RYR1	c.1597C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685434	{33767344}	\N	\N	PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777579	384	CYP2C19	*26	\N	Decreased function	\N	\N	777578	{19661214,25001882}	Limited	\N	CYP2C19*26 is assigned decreased function based on limited evidence in a heterozygous subject and in vitro studies. CYP2C19*26 was first described in a subject also carrying the CYP2C19*2 allele and demonstrated decreased omeprazole metabolism compared to wildtype and CYP2C19 *1/*2 or CYP2C19*1/*3 subjects based on the plasma metabolite ratio. This result was correlated with an in vitro study which showed CYP2C19*26 demonstrated decreased intrinsic clearance compared to wildtype with mephenytoin and omeprazole substrates (19661214). An additional in vitro study using a different cell system similarly found CYP2C19*26 demonstrated decreased intrinsic clearance compared to wildtype with mephenytoin and clopidogrel substrates (25001882). Therefore, consensus among experts was decreased function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685541	175	RYR1	c.6388G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685540	{35849058}	\N	\N	PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": 0.0001925, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002413}	f
3685555	175	RYR1	c.6544A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685554	{35849058}	\N	\N	PS4_Sup, PM1	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
7219575	14	NAT2	*72	Slow	Decreased function	\N	\N	7219574	{15564878}	Moderate	\N	NAT2*72 is assigned decreased function based on moderate evidence. NAT2*72 is defined by the core SNVs c.67A>C (p.T23P) and c.341T>C (p.I114T). c.341T>C (p.I114T) defines NAT2*5 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. In vitro studies also show that NAT2*5 (which contains the core SNV c.341T>C, p.I114T) is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*72 would presumably be degraded in the same manner. Additionally, five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. There is no literature describing function for c.67A>C. Seven out of ten variant effect predictors tested by CPIC staff predict that c.67A>C (p.T23P) impairs protein function. NAT2*72 is assigned decreased function based on c.341T>C. Despite this, the combinatorial effects associated with c.341T>C and c.67A>C are uncertain.	\N	f
3685679	175	RYR1	c.7385C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685678	{33767344}	\N	\N	PP3_Mod	{"Latino": 0.00006543, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.0002068, "Sub-Saharan African": 0.00002413}	f
779225	363	RYR1	c.7522C>G	Variant of uncertain significance	Uncertain function	\N	n/a	779224	{}	\N	\N	PS3_Mod, PM5_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6481235	30	NAT2	*39	Slow	Decreased function	\N	\N	6481234	{24533708,19909761}	Moderate	\N	NAT2*39 is assigned decreased function based on moderate evidence. NAT2*39 is characterized by the core SNVs c.590G>A (p.R197Q), c.803G>A (p.R268K), and c.838G>A (p.V280M). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. Published in silico modeling predicts that c.838G>A (p.V280M) impairs protein function based on the exposure of hydrophobic residues that may facilitate protein aggregation and/or targeted protein degradation (19909761). NAT2*39 was identified in one patient (genotyped NAT2*4/*39) in a NAT2 phenotyping study using isoniazid. This patient was classified as an intermediate acetylator and this study showed lower acetyl-INH/INH ratios for intermediate acetylators compared to rapid acetylators, defined as individuals homozygous for NAT2 increased function alleles *1 or *4 or heterozygous NAT2*1/*4 (24533708). Four out of ten variant effect predictors tested by CPIC staff predict that c.838G>A (p.V280M) impairs protein function, which is supported by published in silico predictions (27984508). c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A impairs protein function. Thus, NAT2*39 is assigned decreased function based on c.590G>A. Despite this, it remains unknown whether there are any combinatorial effects associated with c.838G>A and c.590G>A.	\N	f
3685701	175	RYR1	c.7787C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685700	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": 0.00001475, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685713	175	RYR1	c.8054C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685712	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685787	175	RYR1	c.10747G>C	Benign	Normal function	\N	n/a	3685786	{33767344}	\N	\N	BA1	{"Latino": 0.007591, "American": 0.002193, "European": 0.018851086, "East Asian": 0.0003858, "Near Eastern": 0.000288, "Central/South Asian": 0.02488, "Sub-Saharan African": 0.003764}	f
6481283	30	NAT2	*63	Slow	Decreased function	\N	\N	6481282	{}	Moderate	\N	NAT2*63 is assigned decreased function based on moderate evidence. NAT2*63 is characterized by the core SNVs c.590G>A (p.R197Q), c.650T>A (p.F217Y) and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.650T>A (p.F217Y). Seven out of ten variant effect predictors tested by CPIC staff predict c.650T>A (p.F217Y) impairs protein function. c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. Thus, NAT2*63 is assigned decreased function based on c.590G>A. Despite this, the combinatorial effects associated with c.650T>A and c.590G>A are uncertain.	\N	f
3685325	175	RYR1	c.178G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685324	{35849058}	\N	\N	PS4_Sup, PM1	{"Latino": null, "American": null, "European": 0.00001475, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
2677014	121	CYP2D6	*151	\N	\N	\N	\N	2677013	\N	\N	\N	\N	\N	f
3685693	175	RYR1	c.7771C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685692	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00007262}	f
777685	384	CYP2C9	*9	Normal function	Normal function	\N	1.0	777684	{23752738,15284535,21811894,28758225,16220110,19164093,20716240}	Strong	\N	CYP2C9*9 is assigned normal function based on strong evidence in heterozygous patients, homozygous patients, and in vitro studies. Twenty-one subjects with CYP2C9 *1/*9 genotype and three subjects with CYP2C9 *9/*9 genotype had similar urinary excretion of a phenytoin metabolite compared to CYP2C9 *1/*1 subjects following a phenytoin 300mg dose, demonstrating CYP2C9*9 is not associated with decreased phenytoin metabolism (16220110). Seven subjects with CYP2C9 *1/*9 genotype had similar acenocoumarol plasma concentrations 8 and 24 hours after an 8mg dose compared to CYP2C9 *1/*1 subjects (21811894). Seven patients on a stable dose of warfarin with CYP2C9 *1/*9 genotype had a similar maintenance warfarin dose compared to CYP2C9 *1/*1 patients (20716240). In vitro studies demonstrated CYP2C9*9 intrinsic clearance or enzyme activity was similar compared to wildtype using warfarin and tolbutamide substrates (23752738, 15284535). Although one in vitro study showed CYP2C9*9 demonstrated decreased enzyme activity with a 7-ethoxycoumarin substrate compared to wildtype (28758225), the experts did not find this result convincing as no clinical difference was seen in patients taking acenocoumarol or warfarin, or in another in vitro study using a warfarin substrate as previously described. Although one study using the polyphen computational program to predict the functional effect of the SNP defining CYP2C9*9 predicted the substitution as possibly damaging to enzyme function, the authors also noted that this effect has not been shown in clinical phenotypic studies (19164093). Therefore, consensus among experts was normal function with an activity value of 1 based on strong evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.1295592, "African American/Afro-Caribbean": 0.0}	f
3685493	175	RYR1	c.4400A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685492	{33767344}	\N	\N	BP4	{"Latino": null, "American": null, "European": 0.0000149, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685537	175	RYR1	c.6377G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685536	{35849058}	\N	\N	PS4_Sup, PM1	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685601	175	RYR1	c.7036G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685600	{35849058}	\N	\N	PS4_Mod, PM1, PP3_Mod	{"Latino": null, "American": null, "European": 0.00001471, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779217	363	RYR1	c.7361G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779216	{33767344}	\N	\N	PS3_Mod, PS4, PM1, PP1_St, PP3_Mod, BS2_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6481209	30	NAT2	*19	Slow	Decreased function	\N	\N	6481208	{18680467,12222688,9173883}	Limited	\N	NAT2*19 is assigned decreased function based on limited evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*19 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*19 is characterized by the core SNVs c.190C>T (p.R64W) and c.803G>A (p.R268K). c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. In vitro studies of c.190C>T (p.R64W) have shown decreased protein expression, decreased thermostability, and significantly decreased N-acetyltransferase activity toward sulfamethazine (12222688). An additional in vitro study found that amino acid substitutions of arginine 64 to alanine, lysine, methionine, or glutamine (the latter of which defines NAT2*14) significantly decreased NAT2 protein stability and N-acetyltransferase activity toward p-aminosalicylic acid and all but p.R64K showed decreased N-acetyltransferase activity toward sulfamethazine (9173883). These results highlight the importance of the p.R64 residue for proper NAT2 catalytic activity. Published in silico modeling predicts that c.190C>T (p.R64W) decreases NAT2 protein stability, decreases flexibility and hydrogen bond capacity, and increases hydrophobicity and aromaticity resulting in a loss of electrostatic interactions (18680467). Similarly, six out of ten variant effect predictors tested by CPIC staff predict that c.190C>T (p.R64W) impairs NAT2 protein function.	\N	f
2784573	162	CYP4F2	*4	\N	\N	\N	\N	2784572	\N	\N	\N	\N	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
2784575	162	CYP4F2	*5	\N	\N	\N	\N	2784574	\N	\N	\N	\N	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685839	175	RYR1	c.12242C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685838	{35849058}	\N	\N	None	{"Latino": 0.0003275, "American": null, "European": 0.0000294, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6481269	30	NAT2	*56	Slow	Decreased function	\N	\N	6481268	{}	Moderate	\N	NAT2*56 is assigned decreased function based on moderate evidence. NAT2*56 is characterized by the core SNVs c.58G>T (p.D20Y), c.590G>A (p.R197Q) and c.803G>A (p.R268K). c.803G>A (p.R268K) defines NAT2*4, formerly considered the reference allele, which has repeatedly shown increased function in vivo and in vitro. There is no literature describing function for c.58G>T (p.D20Y). Eight out of ten variant effect predictors tested by CPIC staff predict that c.58G>T (p.D20Y) impairs protein function. c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. Thus, NAT2*56 is assigned decreased function based on c.590G>A. Despite this, the combinatorial effects associated with c.58G>T and c.590G>A are uncertain.	\N	f
6481253	30	NAT2	*48	Slow	Decreased function	\N	\N	6481252	{17434923,18680467,17264801}	Limited	\N	NAT2*48 is assigned decreased function based on limited evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*48 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". In vitro evidence demonstrates that NAT2*48 N-acetylation activity is undetectable when using sulfamethazine as a substrate. NAT2*48 mRNA expression levels are comparable to NAT2*4, but protein expression is undetectable in mammalian cells (17264801, 17434923). Despite the undetectable enzymatic activity, the authors concluded that NAT2*48 exhibits decreased function rather than no function. Similarly, the committee could not come to consensus on a call of no function due to the lack of in vivo data supporting a complete loss of function. Published in silico modeling suggests that c.364G>A (p.D122N) disrupts the catalytic triad and the stability of the active site loop (18680467). Eight out of ten variant effect predictors tested by CPIC staff predict that c.364G>A (p.D122N) impairs protein function.	\N	f
779314	362	SLCO1B1	*19	\N	Uncertain function	\N	\N	779313	{15226675,22147369,29898760,23311897}	Inadequate	\N	SLCO1B1*19 is assigned uncertain function based on no in vitro evidence and limited clinical data. One clinical study showed 1 heterozygous subject treated with pravastatin had similar pharmacokinetic parameters to subjects with wildtype alleles (15226675). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779324	362	SLCO1B1	*24	\N	Uncertain function	\N	\N	779323	{22147369}	Inadequate	\N	SLCO1B1*24 is assigned uncertain function based on no in vitro evidence and limited clinical data. One clinical study showed 2 heterozygous subjects treated with high-dose methotrexate had similar methotrexate clearance to subjects with wildtype alleles (22147369). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779075	364	NUDT15	*6	Decreased function	No function	\N	\N	779074	{26878724,28903549,30728528,32308129,32372428,32598049,32221476,32873882,35156873,33481917,37454061,33753169,34665987,36873097,30806694}	Moderate	14.9 Vmax/Km	NUDT15*6 is assigned no function based on moderate evidence. In vitro studies using a bacterial expression system found that NUDT15.6 exhibits decreased enzymatic activity using TGTP or TdGTP as substrates compared to NUDT15.1 (26878724, 33753169). Additionally, NUDT15.6 exhibits reduced protein thermostability compared to NUDT15.1 (26878724, 33753169). The destabilizing effects of c.55_56insGAGTCG (p.V18_V19insGV) were confirmed using an experimentally derived crystal structure of NUDT15.6 (33753169). NUDT15*1/*6 patients have been shown to tolerate lower doses of thiopurines (32221476, 34665987) and one patient genotyped NUDT15*3/*6 tolerated a significantly lower thiopurine dose (32873882) compared to NUDT15*1/*1 patients. Patients carrying a NUDT15*6 allele also exhibit increased incidence of adverse reactions and increased therapy interruption compared to NUDT15*1/*1 patients (28903549, 30728528, 37454061, 34665987, 36873097, 30806694). NUDT15*6 is characterized by the in-frame insertion c.55_56insGAGTCG (p.V18_V19insGV), which is predicted to impair protein function by CADD and PhD-SNPg	{"Latino": 0.0015, "European": 0.003, "East Asian": 0.013, "Central/South Asian": 0.002}	f
1002706	356	SLCO1B1	*47	\N	No function	\N	\N	1002705	{33658230,11477075,32961594,21245207}	Limited	\N	SLCO1B1*47 is assigned no function due to no literature describing function of this allele. It contains 3 variants, rs2306283, rs4149056, both included in the no function *15 allele and rs72559747. One in vitro study found normal protein expression and transport for the rs72559747 variant (33658230). Based on evidence supporting the function of rs4149056C>T (11477075, 32961594, 21245207), SLCO1B1*47 is assigned no function with limited evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1357094	345	SLCO1B1	*49	\N	No function	\N	\N	1357093	{22232210}	Limited	\N	SLCO1B1*48 is assigned no function due to evidence supporting a partial gene deletion (22232210). Therefore, consensus among experts was no function due to limited evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777709	384	CYP2C9	*21	Uncertain function	Uncertain function	\N	n/a	777708	{23752738}	Inadequate evidence	\N	CYP2C9*21 is assigned uncertain function due to inadequate evidence. In one in vitro study, CYP2C9*21 demonstrated no enzyme activity compared to wildtype with a warfarin and tolbutamide substrate (23752738). Therefore, consensus among experts was uncertain function due to insufficient evidence.	{"Latino": 0.00030, "American": null, "European": 0.00010, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779095	142	NUDT15	*16	\N	Uncertain function	\N	\N	779094	{32094176}	Inadequate	\N	NUDT15*16 is assigned uncertain function based on inadequate evidence. An in vitro study expressed NUDT15*16 in HEK293 cells and found that NUDT15.16 protein levels were significantly decreased compared to NUDT15.1, and NUDT15*16 increased thiopurine sensitivity in cells (32094176). Seven out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*16-defining SNV, c.88C>T (p.L30V), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
3685805	175	RYR1	c.11314C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685804	{33767344}	\N	\N	PS4_Sup, PM5_Sup, PP3_Mod	{"Latino": 0.00006547, "American": null, "European": 0.0000294, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685803	175	RYR1	c.11315G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685802	{33767344}	\N	\N	PS4_Mod, PP1_St, PP3_Mod, BS2_Mod	{"Latino": null, "American": null, "European": 0.00001471, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002414}	f
3685829	175	RYR1	c.12028G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685828	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "American": null, "European": 0.00009436, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00009667}	f
3685891	175	RYR1	c.13994_13995delTCinsCT	Variant of uncertain significance	Uncertain function	\N	n/a	3685890	{35849058}	\N	\N	PS2_PM6_Sup, PM1_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777707	384	CYP2C9	*20	Uncertain function	Uncertain function	\N	n/a	777706	{23752738}	Inadequate evidence	\N	CYP2C9*20 is assigned uncertain function due to inadequate evidence. In one in vitro study, CYP2C9*20 demonstrated decreased enzyme activity compared to wildtype with a warfarin and tolbutamide substrate (23752738). Therefore, consensus among experts was uncertain function due to insufficient evidence.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779399	362	TPMT	*3B	\N	No function	\N	\N	779398	{16220112,9177237,18708949,8644731,8561894,9246020,23585236,29387964,33928426,31005613,15967990,33205673,12217596,16691038}	Definitive	\N	TPMT*3B is assigned no function based on definitive evidence. Erythrocytes from individuals heterozygous for TPMT*3B exhibited intermediate enzymatic activity (9246020, 23585236, 33928426, 31005613, 12217596, 16691038), while erythrocytes from individuals heterozygous for TPMT*3B in combination with another no function allele exhibited low enzymatic activity (31005613). Patients carrying TPMT*3B alleles exhibited increased plasma concentrations of TGNs, increased DNA-incorporated thioguanine, decreased plasma concentrations of methylated metabolites, and tolerated lower doses of thiopurines (23585236, 29387964, 33928426, 33205673). In vitro studies demonstrate that TPMT.3B exhibited decreased protein expression, decreased protein stability, and enzymatic activity is decreased by 75-100% relative to TPMT.1 in yeast (9177237, 8644731) and mammalian (16220112, 18708949, 8561894) cells. TPMT.3B decreased protein expression is attributed to rapid degradation by the proteasome (16220112, 9177237) as well as TPMT.3B aggresome formation (15967990). Seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*3B-defining SNV, c.460G>A (p.A154T), impairs protein function.	{"Latino": 0.002382896, "European": 0.0028341785, "East Asian": 0.0, "Near Eastern": 0.004721087, "Central/South Asian": 0.0017308706, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
779409	362	TPMT	*7	\N	No function	\N	\N	779408	{9831928,9711875,13679074,16220112,18708949}	Limited	\N	TPMT*7 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*7 exhibited intermediate activity (9711875, 9831928). In vitro studies using mammalian cell systems found that TPMT.7 enzymatic activity is either comparable (16220112) or decreased by 90% (13679074, 1870894) relative to TPMT.1, and protein expression levels are comparable to TPMT.1 in mammalian (16220112, 18708949) and yeast cells (13679074). Additionally, studies agree that TPMT.7 exhibited decreased affinity for 6-TG in vitro (13679074, 18708949). One out of ten variant effect predictors tested by CPIC staff predicts that the TPMT*7-defining SNV, c.681T>G (p.H227Q), impairs protein function. Despite conflicting in vitro evidence, the experts agreed to assign no function based on the available clinical data.	{"Latino": 0.0, "European": 0.000015974565, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779411	362	TPMT	*8	\N	Decreased function	\N	\N	779410	{9931346,16220112,18708949,27564568,29785012,30023734,33118454,34412101,39182670}	Moderate	\N	TPMT*8 is assigned decreased function based on moderate evidence. Clinically, erythrocytes from individuals genotyped TPMT*1/*8 exhibited intermediate enzymatic activity (9931346, 27564568, 39182670). Erythrocytes from individuals genotyped TPMT*8/*33 or TPMT*8/*8 also exhibited intermediate enzymatic activity (33118454), while individuals genotyped TPMT*3A/*8 or TPMT *3C/*8 exhibited decreased activity by 16% and 42%, respectively, relative to normal metabolizers. Despite these observations, thiopurine dose intensity is not significantly different between individuals genotyped TPMT*1/*8 and TPMT*1/*1 (27564568, 29785012, 34412101). In vitro studies in mammalian cell systems found that TPMT.8 protein expression is comparable (16220112) or increased (18708949) compared to TPMT.1. These results are corroborated by a study which found TPMT.8 protein abundance is comparable to TPMT.1 (29785012). Enzyme kinetic analysis indicates that TPMT.8 activity is decreased by 28% relative to TPMT.1 (16220112), while another study found that TPMT.8 enzymatic activity is not statistically different from TPMT.1 and that TPMT.8 has increased affinity for 6-TG (18708949). Recombinant TPMT.8 expressed and purified from bacterial cells exhibited identical biophysical characteristics to TPMT.1 (30023734). Ten out of ten variant effect predictors tested by CPIC staff predict that the TPMT*8-defining SNV, c.644G>A (p.R215H), does not impair protein function. Despite conflicting in vitro evidence, the experts agreed to assign decreased function based on the available clinical data.	{"Latino": 0.001191, "European": 0.000104547704, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.00009375629, "Sub-Saharan African": 0.024, "African American/Afro-Caribbean": 0.00648}	f
779042	65	IFNL3	rs12979860 reference (C)	\N	\N	\N	\N	779041	\N	\N	\N	\N	\N	t
779044	65	IFNL3	rs12979860 variant (T)	\N	\N	\N	\N	779043	\N	\N	\N	\N	\N	f
777717	384	CYP2C9	*25	No function	No function	\N	0.0	777716	{23752738,16788382}	Limited	\N	CYP2C9*25 is assigned no function based on limited evidence. CYP2C9*25 is defined by a deletion which leads to a frameshift resulting in an early stop codon and truncated protein. This was demonstrated in an in vitro study where CYP2C9*25 had similar mRNA levels compared to wildtype but no protein expression (16788382). CYP2C9*25 was not included in subsequent in vitro studies because it is it is a null allele resulting in no protein formation (23752738). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal and decreased function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.002, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
779083	142	NUDT15	*10	\N	No function	\N	\N	779082	{}	Limited	\N	NUDT15*10 is assigned no function based on limited evidence. While there is no literature describing function for NUDT15*10, c.2T>C is predicted to disrupt protein translation due to the loss of the canonical start codon, and there is no alternative start codon available. Three out of seven variant effect predictors tested by CPIC staff predict that the NUDT15*10 SNV (c.2T>C) impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
777727	384	CYP2C9	*30	Decreased function	Decreased function	\N	0.5	777726	{23752738,19541829,16788382}	Limited	\N	CYP2C9*30 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*30 demonstrated decreased clearance compared to wildtype. These studies used different cell systems and substrates included warfarin, tolbutamide, diclofenac, losartan, and glimepiride (23752738, 19541829, 16788382). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0015598785, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777739	384	CYP2C9	*36	Uncertain function	Uncertain function	\N	n/a	777738	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25951663,25924705,27163851,23844998}	Inadequate evidence	\N	CYP2C9*36 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C9*36 demonstrated enzyme activity ranging from markedly decreased to markedly increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25951663, 25924705, 27163851, 23844998). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778219	377	CYP3A5	*1	\N	Normal function	\N	\N	778218	{12893984}	\N	\N	12893984: testosterone, nifedipine (in vitro)	{"Latino": 0.17279238, "European": 0.07410407, "East Asian": 0.25355196, "Near Eastern": 0.121941924, "Central/South Asian": 0.32672024, "Sub-Saharan African": 0.47940862, "African American/Afro-Caribbean": 0.4528548}	t
778223	377	CYP3A5	*3	\N	No function	\N	\N	778222	{15179407}	\N	\N	15179407: midalozam (in vivo)	{"Latino": 0.7651353, "European": 0.9243815, "East Asian": 0.7457923, "Near Eastern": 0.83611745, "Central/South Asian": 0.67327976, "Sub-Saharan African": 0.24094562, "African American/Afro-Caribbean": 0.31597915}	f
778229	376	CYP3A5	*6	\N	No function	\N	\N	778228	{11279519}	\N	\N	\N	{"Latino": 0.037054006, "European": 0.0015144596, "East Asian": 0.0006557377, "Near Eastern": 0.038085584, "Central/South Asian": 0.0, "Sub-Saharan African": 0.19323565, "African American/Afro-Caribbean": 0.11116607}	f
2677012	121	CYP2D6	*150	\N	\N	\N	\N	2677011	\N	\N	\N	\N	\N	f
777751	384	CYP2C9	*42	No function	No function	\N	0.0	777750	{24077631,24118918,25142737,25144335,25476996,25614704,25832633,25951663,25884291,25924705,27163851,23844998}	Limited	\N	CYP2C9*42 is assigned no function based on limited evidence in one heterozygous patient and in vitro studies. One subject with CYP2C9*1/*42 genotype exhibited twice the AUC and less than half the oral clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704). Multiple in vitro studies found CYP2C9*42 demonstrated markedly decreased clearance compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25951663, 25884291, 25924705, 27163851, 23844998, 25614704). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function or decreased function alleles.	{"Latino": 0.00010, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.01, "Near Eastern": 0.00054534996, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777761	384	CYP2C9	*47	Uncertain function	Uncertain function	\N	n/a	777760	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25924705,25951663,27163851,23844998}	Inadequate evidence	\N	CYP2C9*47 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C9*47 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25924705, 25951663, 27163851, 23844998). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778231	377	CYP3A5	*7	\N	No function	\N	\N	778230	{14515058}	\N	\N	14515058: midazolam (in vitro)	{"Latino": 0.02501835, "European": 0.0, "East Asian": 0.0, "Near Eastern": 0.00385505, "Central/South Asian": null, "Sub-Saharan African": 0.08641013, "African American/Afro-Caribbean": 0.12}	f
778233	376	CYP3A5	*8	\N	Unknown function	\N	\N	778232	{}	\N	\N	\N	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777765	384	CYP2C9	*49	Uncertain function	Uncertain function	\N	n/a	777764	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25951663,27163851,23844998}	Inadequate evidence	\N	CYP2C9*49 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C9*49 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25951663, 27163851, 23844998). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777767	384	CYP2C9	*50	Decreased function	Decreased function	\N	0.5	777766	{24077631,24118918,25142737,25144335,25951663,25476996,25832633,25884291,25924705,27163851,23844998}	Limited	\N	CYP2C9*50 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*50 demonstrated decreased clearance compared to wildtype for multiple substrates (24077631, 24118918, 25476996, 25144335, 25951663, 25832633, 25884291, 27163851, 25142737, 25924705, 23844998). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777769	384	CYP2C9	*51	Uncertain function	Uncertain function	\N	n/a	777768	{24077631,24118918,25142737,25144335,25951663,25476996,25832633,25884291,25924705,27163851,23844998}	Inadequate evidence	\N	CYP2C9*51 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C9*51 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 25142737, 25144335, 25951663, 25476996, 25832633, 25884291, 25924705, 27163851, 23844998). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779510	200	VKORC1	rs9923231 variant (T)	\N	\N	\N	\N	779509	\N	\N	\N	\N	{"Latino": 0.39330897, "American": 0.6160526, "European": 0.4132605, "East Asian": 0.8664911, "Near Eastern": 0.45357868, "Central/South Asian": 0.15644945, "Sub-Saharan African": 0.107742354, "African American/Afro-Caribbean": 0.101332836}	f
779508	200	VKORC1	rs9923231 reference (C)	\N	\N	\N	\N	779507	\N	\N	\N	\N	{"Latino": 0.606691, "American": 0.38394737, "European": 0.58673954, "East Asian": 0.13350892, "Near Eastern": 0.5464213, "Central/South Asian": 0.84355056, "Sub-Saharan African": 0.89225763, "African American/Afro-Caribbean": 0.89866716}	t
1508725	366	ABCG2	rs2231142 reference (G)	\N	Normal function	\N	\N	1508724	{}	\N	\N	\N	{"Latino": 0.7756, "American": 0.8, "European": 0.8964, "Oceanian": 0.7952753, "East Asian": 0.6929, "Near Eastern": 0.9347, "Central/South Asian": 0.9068, "Sub-Saharan African": 0.994154, "African American/Afro-Caribbean": 0.9651338}	f
778235	376	CYP3A5	*9	\N	Unknown function	\N	\N	778234	{}	\N	\N	\N	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777267	384	CACNA1S	c.3257G>A	Uncertain function	Malignant Hyperthermia associated	\N	\N	777266	{9199552,11260227,12411788,16163667,15201141}	\N	\N	9199552: positive IVCT; 11260227: positive IVCT; 12411788: positive IVCT; 16163667: positive IVCT; 15201141: Similar to that observed for MH mutations in RYR1, the R1086H MH mutation in the 1S-subunit of the skeletal muscle DHPR increases the sensitivity of the calcium release mechanism to activation by both pharmacological (caffeine) and endogenous (voltage sensor) activators. Threshold for caffeine-induced calcium release is approximately fivefold lower in R1086H- expressing myotubes. Increased "sensitivity" of RYR1 to activation by caffeine may be a consequence of an elevated resting calcium level in R1086H- expressing myotubes. The data suggest that the intracellular III-IV linker of the DHPR acts as a negative regulatory module for release channel activation and that the R1086H MH mutation in 1S disrupts this critical negative allosteric regulatory mechanism.	{"Latino": 0.00002891, "European": 0.0, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0}	f
777356	234	CFTR	L206W	\N	ivacaftor responsive	\N	\N	777355	{}	\N	\N	\N	\N	f
777358	234	CFTR	P67L	\N	ivacaftor responsive	\N	\N	777357	{}	\N	\N	\N	\N	f
777372	234	CFTR	R74W	\N	ivacaftor responsive	\N	\N	777371	{}	\N	\N	\N	\N	f
777807	366	CYP2C9	*70	Uncertain function	Uncertain function	\N	n/a	777806	{33536773}	Inadequate evidence	\N	CYP2C9*70 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variants present in CYP2C9*70 are predicted to be deleterious in SIFT and and benign in Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777809	366	CYP2C9	*71	Uncertain function	Uncertain function	\N	n/a	777808	{}	Inadequate evidence	\N	CYP2C9*71 is assigned uncertain function due to limited literature describing function of this allele. This allele has the same variants as *10 (uncertain function) and *12 (decreased function) but no literature supporting the function for *71. Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777308	234	CFTR	ivacaftor non-responsive CFTR sequence	\N	ivacaftor non-responsive	\N	\N	777307	{}	\N	\N	\N	\N	f
777316	234	CFTR	711+3A->G	\N	ivacaftor responsive	\N	\N	777315	{}	\N	ACMG screening panel	\N	\N	f
777322	234	CFTR	D110E	\N	ivacaftor responsive	\N	\N	777321	{}	\N	\N	\N	\N	f
777324	234	CFTR	D110H	\N	ivacaftor responsive	\N	\N	777323	{}	\N	\N	\N	\N	f
777332	234	CFTR	E193K	\N	ivacaftor responsive	\N	\N	777331	{}	\N	\N	\N	\N	f
777334	234	CFTR	E56K	\N	ivacaftor responsive	\N	\N	777333	{}	\N	\N	\N	\N	f
777348	234	CFTR	G178R	\N	ivacaftor responsive	\N	\N	777347	{}	\N	\N	\N	\N	f
777423	384	CYP2B6	*1	\N	Normal function	\N	\N	777422	{}	\N	\N	\N	{"Latino": 0.49736506, "European": 0.49070138, "Oceanian": 0.34000003, "East Asian": 0.64004594, "Near Eastern": 0.476, "Central/South Asian": 0.6084849, "Sub-Saharan African": 0.31465185, "African American/Afro-Caribbean": 0.41346413}	t
777441	384	CYP2B6	*10	\N	Uncertain function	\N	\N	777440	{21746968,30201214}	Inadequate	\N	CYP2B6*10 (c.62A>T, p.Q21L and c.64C>T, p.R22C) - Uncertain function: CYP2B6*10 is assigned uncertain function. In vitro studies using cDNA expression systems (21746968, 30201214) demonstrated decreased enzyme activity compared to the *1 reference. However, consensus among experts was uncertain function based on inadequate evidence as it could not be determined if diplotypes containing this allele would be phenotypically distinct from diplotypes comprising two normal function alleles.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779479	142	TPMT	*42	\N	No function	\N	\N	779478	{31005613,32865889}	Strong	\N	TPMT*42 is assigned no function based on strong evidence. Erythrocytes from individuals genotyped TPMT*1/*42 exhibited intermediate enzymatic activity (31005613, 32865889), while erythrocyte from an individual genotyped TPMT*3A/*42 exhibited low enzymatic activity (31005613, 32865889).The TPMT*42-defining SNV, c.95_96insA, results in a frameshift of the coding sequence and the creation of a premature stop codo, which is predicted to undergo nonsense-mediated decay. The variant effect predictors, CADD and PhD-SNPg, predict that c.95_96insA (p.Trp33ValfsTer26) impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777461	384	CYP2B6	*21	No or decreased function	Uncertain function	\N	\N	777460	{16272958,20517174,21746968,30201214}	Inadequate	\N	CYP2B6*21 (c.1282C>A, p.P428T) – Uncertain function: CYP2B6*21 is assigned uncertain function. In vitro studies using cDNA expression systems found no or severely decreased enzyme activity for CYP2B6*21 (20517174, 21746968, 16272958, 30201214). However, there was no in vivo data available or data in human liver microsomes. Therefore, the consensus among experts was uncertain function based on inadequate evidence.	{"Latino": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0127297295, "African American/Afro-Caribbean": 0.0}	f
779451	362	TPMT	*28	\N	No function	\N	\N	779450	{20945351}	Limited	\N	TPMT*28 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*3A/*28 exhibited very low enzymatic activity (20945351). The patient exhibited a plasma concentration of 6-TGN above the therapeutic range and MMP was undetectable (20945351). Seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*28-defining SNV, c.349G>C (p.G117R), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777427	384	CYP2B6	*3	\N	Uncertain function	\N	\N	777426	{12642465,30201214}	Inadequate	\N	CYP2B6*3 (c.777C>A, p.S259R) - Uncertain function: CYP2B6*3 is assigned uncertain function. In vitro studies using cDNA expression systems demonstrated that CYP2B6*3 had similar enzyme activity or slightly decreased activity compared to the *1 reference (12642465, 30201214). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": 0.0018442405, "European": 0.00213266, "Oceanian": 0.0, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0024408852, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0022592593}	f
777445	384	CYP2B6	*12	No function	No function	\N	\N	777444	{15190123,20517174,21746968,30201214}	Limited	\N	CYP2B6*12 (c.296G>A, p.G99E) - No function: CYB2B6*12 is assigned no function. Multiple in vitro studies using human liver microsomes (15190123) and cDNA expression systems (20517174, 21746968, 30201214) found that CYP2B6*12 has no protein expression or enzyme activity compared to the *1 reference with various substrates. Therefore, consensus among experts was no function based on limited evidence.	{"Latino": 0.000541036, "European": 0.00006630849, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777465	383	CYP2B6	*23	\N	Uncertain function	\N	\N	777464	{21746968,30201214}	Inadequate	\N	CYP2B6*23 (c.1375A>G, p.M459V) – Uncertain function: CYP2B6*23 is assigned uncertain function. One in vitro cDNA expression study found evidence of higher expression which did not cause a change in activity (30201214), while another study showed slightly increased activity (21746968). Therefore, the consensus among experts was uncertain function based on inadequate evidence.	{"Latino": 0.0, "European": 0.00005515508, "Oceanian": null, "East Asian": 0.002063492, "Near Eastern": null, "Central/South Asian": 0.000043009855, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
779453	362	TPMT	*29	\N	No function	\N	\N	779452	{22447118}	Limited	\N	TPMT*29 is assigned no function based on limited evidence. The TPMT*29 -defining SNV, c.2T>C (p.M1T), is predicted to disrupt protein translation due to the loss of the canonical start codon, and there is no alternative start codon available. An individual genotyped TPMT*1/*29 was predicted to be an intermediate metabolizer (22447118). Five out of eight variant effect predictors tested by CPIC staff predict that c.2T>C (p.M1T) impairs protein function.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0002899, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779069	364	NUDT15	*3	\N	No function	\N	\N	779068	{26878724,28659275,27530327,29519865,37488179,31645647,32094176,38246006,28088792,27604507,34636169,34480209,35067667,28445187,32372428,33481917,32598049,28903549,32308129,29720126,32873882,36858569,35156873,32221476,31507415,27577869,27416873,26033531,30728528,37454061,39688234,33753169}	Definitive	undetectable enzymatic activity in vitro	NUDT15*3 is assigned no function based on definitive evidence. In vitro studies using a bacterial expression system have found that NUDT15.3 enzymatic activity is significantly decreased or undetectable (26878724, 28659275, 33753169) and protein stability is decreased (29519865, 27530327, 33753169). In mammalian cells, NUDT15.3 protein expression is decreased (32094176, 38246006) and the protein was shown to be actively degraded by the proteasome (27530327). Additionally, NUDT15*1/*3 or NUDT15*3/*3 cell lines exhibit increased levels of DNA-TG and increased sensitivity to 6-MP compared to NUDT15*1/*1 cell lines (34636169). These data are supported by published structural analysis which indicates that the NUDT15*3 SNV, c.415C>T (p.R139C), disrupts the α-helix loop and the base of the substrate binding pocket, and may form a disulfide bond with residue 140, decreasing enzymatic activity (28088792). While the formation of a disulfide bond was not observed, the destabilizing effects of c.415C>T (p.R139C) were confirmed using an experimentally derived crystal structure of NUDT15.3 (33753169). Four out of nine variant effect predictors tested by CPIC staff predict that c.415C>T (p.R139C) impairs protein function. Mouse models of NUDT15*1/*3 or NUDT15*3/*3 are more susceptible to MP treatment and exhibit increased cytopenia and bone marrow failure compared to NUDT15*1/*1 mice (31645647). Additionally, HSCs derived from the bone marrow of NUDT15*3/*3 mice exhibit decreased viability and an upregulation of genes associated with DNA damage response and the cell cycle (37488179). The level of dose-normalized DNA-TG is increased in NUDT15*1/*3 or NUDT15*3/*3 patients (26878724, 34480209, 28445187, 33481917, 39688234) relative to NUDT15*1/*1 patients. Lastly, NUDT15*1/*3 or NUDT15*3/*3 patients tolerate significantly lower thiopurine doses compared to NUDT15*1/*1 patients (26878724, 33481917, 32598049, 28903549, 32308129, 29720126, 32873882, 36858569, 35156873, 32221476, 31507415, 27577869, 27416873, 26033531, 39688234) and experience an increased incidence of adverse reactions and/or therapy interruption (30728528, 37454061, 28903549, 36858569).	{"Latino": 0.0075, "European": 0.002, "East Asian": 0.0605, "Central/South Asian": 0.067}	f
777545	384	CYP2C19	*7	\N	No function	\N	\N	777544	{10411572}	Limited	\N	CYP2C19*7 is assigned no function based on limited evidence in a heterozygous subject. CYP2C19*7 is defined by a splicing defect and was described in a subject demonstrating decreased metabolism of mephenytoin based on urine metabolite concentrations after three separate phenotyping studies (10411572). Therefore, consensus among experts was no function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function and decreased function alleles.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.00011376564, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777567	384	CYP2C19	*18	\N	Normal function	\N	\N	777566	{17455109,18312490,21325430,25001882}	Limited	\N	CYP2C19*18 is assigned normal function based on limited evidence. Four in vitro studies found CYP2C19*18 demonstrated similar intrinsic clearance compared to wildtype with mephenytoin, omeprazole, and clopidogrel substrates (17455109, 18312490, 25001882, 21325430). Therefore, consensus among experts was normal function based on limited evidence as it was determined the phenotypes containing this allele would be clinically similar to phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.019867808, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777533	384	CYP2C19	*1	\N	Normal function	\N	\N	777532	{7487078,32602114,22027650,29325448,33237321}	Definitve	\N	CYP2C19*1 is assigned normal function based on definitive evidence. CYP2C19*1 has been studied for more than 20 years and is the most frequently observed allele (7487078, 32602114). CYP2C19*1 has repeatedly demonstrated normal function with numerous substrates and its association with normal function is well-established (22027650, 29325448, 33237321).	{"Latino": 0.7165527, "American": 0.7921841, "European": 0.62514144, "Oceanian": 0.18709892, "East Asian": 0.59554905, "Near Eastern": 0.67225105, "Central/South Asian": 0.543626, "Sub-Saharan African": 0.55150676, "African American/Afro-Caribbean": 0.54676163}	t
777583	384	CYP2C19	*29	\N	Uncertain function	\N	\N	777582	{26153442,30464555,29098786}	Inadequate	\N	CYP2C19*29 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C19*29 demonstrated modest decreased enzyme activity compared to wildtype with mephenytoin, omeprazole, and voriconazole substrates (26153442, 30464555). One in vitro study found increased clearance relative to wild-type for nebivolol (29098786). Consensus was not achieved among experts as data were sparse and conflicting and it was not convincing the magnitude of decreased activity was clinically significant. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00017527216, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779455	362	TPMT	*30	\N	Uncertain function	\N	\N	779454	{23407052,18708949}	Inadequate	\N	TPMT*30 is assigned uncertain function based on inadequate evidence. An in vitro study using a mammalian cell expression system found that TPMT.30 exhibited decreased affinity for 6-TG and 90% decreased enzymatic activity relative to TPMT.1 (18708949). One out of ten variant effect predictors tested by CPIC staff predicts that the TPMT*30-defining SNV, c.106G>A (p.G36S), impairs protein function. Of note, TPMT*30 was originally designated TPMT*24 (23407052).	{"Latino": 0.0001489, "European": 0.000014929322, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
5175551	42	CYP2D6	*173	\N	\N	\N	\N	5175550	\N	\N	\N	\N	\N	f
777601	367	CYP2C19	*39	\N	Uncertain function	\N	\N	777600	{21692664,21325430}	Inadequate	\N	CYP2C19*39 is assigned uncertain function due to inadequate data. Currently, there is no published evidence describing the function of the CYP2C19*39 allele. One in vitro study for 12718A>C (E122A) determined the metabolic activities towards CEC(3-cyano-7-ethoxycoumarin) O-deethylation and concluded decreased function for this variant (21692664) and another study found the Clint for S-mephenytoin is not significantly different and for omeprazole decreased to 0.27 fold compared to no variant (21325430). Consensus was not achieved among experts as data were sparse and not consistent among substrates. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1932986	132	CYP2C9	*76	\N	\N	\N	\N	1932985	\N	\N	\N	\N	\N	f
1932988	132	CYP2C9	*77	\N	\N	\N	\N	1932987	\N	\N	\N	\N	\N	f
1932990	132	CYP2C9	*78	\N	\N	\N	\N	1932989	\N	\N	\N	\N	\N	f
1932992	132	CYP2C9	*79	\N	\N	\N	\N	1932991	\N	\N	\N	\N	\N	f
1932998	132	CYP2C9	*82	\N	\N	\N	\N	1932997	\N	\N	\N	\N	\N	f
1932996	132	CYP2C9	*81	\N	\N	\N	\N	1932995	\N	\N	\N	\N	\N	f
777669	383	CYP2C9	*1	Normal function	Normal function	\N	1.0	777668	{}	\N	\N	\N	{"Latino": 0.86221933, "American": 0.9118648, "European": 0.79275, "Oceanian": 0.95511305, "East Asian": 0.91534376, "Near Eastern": 0.7818267, "Central/South Asian": 0.7721189, "Sub-Saharan African": 0.7255106, "African American/Afro-Caribbean": 0.8710129}	t
777681	384	CYP2C9	*7	Uncertain function	Uncertain function	\N	n/a	777680	{15284535,23752738}	Inadequate evidence	\N	CYP2C9*7 is assigned uncertain function based on inadequate evidence due to conflicting in vitro data and no clinical data. In an in vitro study CYP2C9*7 demonstrated 47% warfarin clearance compared to wildtype, however, similar tolbutamide clearance compared to wildtype was demonstrated in the same study as well as a separate study (23752738, 15284535). Therefore, consensus among experts was not achieved and uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779457	362	TPMT	*31	\N	No function	\N	\N	779456	{23407052,20881512,31005613}	Limited	\N	TPMT*31 is assigned no function based on limited evidence. TPMT.31 exhibited decreased protein expression in patient white blood cells (20881512), and erythrocytes from individuals genotyped TPMT*1/*31 exhibited intermediate enzymatic activity (20881512, 31005613). However, there was no difference in enzymatic activity observed in vitro between recombinant TPMT.1 and TPMT.31 (Vmax=11.1 and 11.8 U/mg, respectively) produced in E coli. (20881512). Five out of ten variant effect predictors tested by CPIC staff predict that the TPMT*31-defining SNV, c.611T>C (p.I204T), impairs protein function. Despite conflicting in vitro evidence, the experts agreed to assign no function based on the available clinical data.	{"Latino": 0.0, "European": 0.0000074631716, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777781	384	CYP2C9	*57	Unknown function	Unknown function	\N	n/a	777780	{}	No evidence	\N	CYP2C9*57 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779459	362	TPMT	*32	\N	Uncertain function	\N	\N	779458	{25564374,23252716}	Inadequate	\N	TPMT*32 is assigned uncertain function based on inadequate evidence. Erythrocytes from a patient genotyped TPMT*1/*32 exhibited intermediate enzymatic activity and the patient's 6-TGN plasma concentration was 694 pmol/8×108 RBCs after receiving 75 mg/m2 6-MP (23252716). An additional patient genotyped TPMT*1/*32 received 43 mg/m2 6-MP, which is 57% of the standard dose, and the patient exhibited a 6-TGN plasma concentration of 1257 pmol/8×108 RBCs (25564374). Erythrocytes from the second patient exhibited normal TPMT enzymatic activity (25564374). Four out of ten variant effect predictors tested by CPIC staff predict that the TPMT*32-defining SNV, c.340G>A (p.E114K), impairs protein function.	{"Latino": 0.0, "European": 0.000029890569, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1933000	132	CYP2C9	*83	\N	\N	\N	\N	1932999	\N	\N	\N	\N	\N	f
1933002	132	CYP2C9	*84	\N	\N	\N	\N	1933001	\N	\N	\N	\N	\N	f
1933004	132	CYP2C9	*85	\N	\N	\N	\N	1933003	\N	\N	\N	\N	\N	f
777673	384	CYP2C9	*3	Decreased function	No function	\N	0.0	777672	{8809086,29283396,20150829,15637526,12742136,10413320,27179628,25775139,19082874,30088221}	Definitive	\N	CYP2C9*3 is assigned no function based on definitive evidence in homozygous and heterozygous patients and in vitro experimental data. CYP2C9*3 has been studied for more than 20 years and its association with impaired function compared to wildtype is well-established (8809086, 29283396, 20150829, 15637526). This allele was previously assigned "decreased function" but after reevaluation of prior and new evidence, CYP2C9*3 is assigned "no function" because its activity is much more decreased compared to CYP2C9*2 for multiple substrates, resulting in the lowest possible designation for the phenotypes observed in homozygous patients (12742136, 10413320, 27179628, 25775139, 19082874, 30088221). Therefore, consensus among experts was no function with an activity value of 0 based on definitive evidence.	{"Latino": 0.040156696, "American": 0.030054513, "European": 0.07554484, "Oceanian": 0.015575971, "East Asian": 0.037616692, "Near Eastern": 0.08251466, "Central/South Asian": 0.10985958, "Sub-Saharan African": 0.011155454, "African American/Afro-Caribbean": 0.01350592}	f
779461	362	TPMT	*33	\N	No function	\N	\N	779460	{23252716,33118454}	Limited	\N	TPMT*33 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*33 exhibited intermediate enzymatic activity and their 6-TGN plasma concentration was 634 pmol/8×108 RBCs after receiving 54 mg/m2 6-MP (23252716). Erythrocytes from individuals genotyped TPMT*8/*33 exhibited intermediate activity (33118454), however the phase was not determined, and it is possible that these individuals are TPMT*1/*46. Eight out of ten variant effect predictors tested by CPIC staff predict that the TPMT*33-defining SNV, c.487C>T (p.R163C), impairs protein function.	{"Latino": 0.00008729, "European": 0.000039384588, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.00003256, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778123	379	CYP2D6	*102	\N	Unknown function	\N	n/a	778122	{}	No Evidence	\N	CYP2D6*102 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0033, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777937	383	CYP2D6	*1	\N	Normal function	\N	1.0	777936	{}	\N	\N	\N	{"Latino": 0.36455274, "American": 0.5164585, "European": 0.28500712, "Oceanian": 0.6170194, "East Asian": 0.25353962, "Near Eastern": 0.24876314, "Central/South Asian": 0.29324096, "Sub-Saharan African": 0.15676576, "African American/Afro-Caribbean": 0.21115738}	t
3685469	175	RYR1	c.3095G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685468	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": 0.0002646, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00004829}	f
779463	362	TPMT	*34	\N	No function	\N	\N	779462	{23252716,33118454}	Moderate	\N	TPMT*34 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*1/*34 exhibited intermediate activity (23252716, 33118454). One of these patients received 44 mg/m2 thioguanine and exhibited a plasma TGN concentration of 3006 pmol/8×108 RBCs (23252716). Seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*34-defining SNV, c.244C>T (p.R82W), impairs protein function.	{"Latino": 0.0, "European": 0.0000074709346, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0005848, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
779465	362	TPMT	*35	\N	Unknown function	\N	\N	779464	{23252704}	No evidence	\N	TPMT*35 is assigned unknown function based on no evidence. There are no in vitro or in vivo functional studies for TPMT*35. Ten out of ten variant effect predictors tested by CPIC staff predict that the TPMT*35-defining SNV, c.200T>C (p.F67S), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685471	175	RYR1	c.3127C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685470	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": 0.0002882, "Central/South Asian": null, "Sub-Saharan African": 0.00002413}	f
779467	362	TPMT	*36	\N	Unknown function	\N	\N	779466	{23252704}	No evidence	\N	TPMT*36 is assigned unknown function based on no evidence. There are no in vitro or in vivo functional studies for TPMT*36. Four out of ten variant effect predictors tested by CPIC staff predict that the TPMT*36-defining SNV, c.595G>A (p.V199I), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685757	175	RYR1	c.9676G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685756	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
1609528	286	CYP2D6	*148	\N	Unknown function	\N	n/a	1609527	{}	No Evidence	\N	CYP2D6*148 is assigned unknown function. CYP2D6*148 is defined by four SNPs of which two are found on the normal function *2 allele. 77G>A (R26H) is found on the *43 allele and the normal function *46 allele, and the forth SNP (3854G>A, E480K) is present on the normal function *27 allele. Since the functional impact of 993C>G is unknown, consensus among experts was unknown function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
1103382	286	CYP2D6	*149	\N	Unknown function	\N	n/a	1103381	{}	No Evidence	\N	CYP2D6*149 is assigned unknown function. CYP2D6*149 is defined by six SNPs of which five are found on the decreased function *29 allele. 993C>G (D97E) has only been found on *149. Since the functional impact of 993C>G is unknown, consensus among experts was unknown function.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.001, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0026, "African American/Afro-Caribbean": 0.0}	f
2091237	284	CYP2D6	*152	\N	Unknown function	\N	n/a	2091236	{}	No Evidence	\N	CYP2D6*152 is assigned unknown function due to no literature describing function of this allele. CYP2D6*152 is defined by a single SNP that is not present in any other star allele.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00052, "African American/Afro-Caribbean": null}	f
2091239	284	CYP2D6	*153	\N	Unknown function	\N	n/a	2091238	{}	No Evidence	\N	CYP2D6*153 is assigned unknown function due to no literature describing function of this allele. CYP2D6*153 is defined by one SNP that is not found on any other star allele.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00052, "African American/Afro-Caribbean": null}	f
778332	377	DPYD	c.61C>T	No function	No function	\N	0.0	778331	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778334	377	DPYD	c.62G>A	Normal function	Normal function	\N	1.0	778333	{24648345}	Moderate	This rsID was orginially described as part of the *12 allele but based on more recent data this designation has changed.	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000037312337, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778340	371	DPYD	c.313G>A	Normal function	Normal function	\N	1.0	778339	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0000136468225, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778342	371	DPYD	c.343A>G	Normal function	Normal function	\N	1.0	778341	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013736458, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778344	371	DPYD	c.451A>G	Normal function	Normal function	\N	1.0	778343	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.011174424, "European": 0.000013283231, "East Asian": 0.00035729833, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778346	371	DPYD	c.496A>G	Normal function	Normal function	\N	1.0	778345	{24648345}	Moderate	\N	5-fluorouracil (in vitro)	{"Latino": 0.036260653, "European": 0.11037259, "East Asian": 0.015562055, "Central/South Asian": 0.085167445, "Sub-Saharan African": 0.03082738, "African American/Afro-Caribbean": 0.03187898}	f
778348	371	DPYD	c.498G>A	Normal function	Normal function	\N	1.0	778347	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778328	229	DPYD	Reference	Normal function	Normal function	\N	1.0	778327	{38129972}	\N	\N	Individual patients have been reported (PMID 38129972) to carry only one of the two SNPs in the HapB3 haplotype (i.e., c.1236G>A without c.1129-5923C>G), suggesting that the two variants are not in complete linkage disequilibrium. To address this, c.1129-5923C>G SNP is listed separately as this is likely the causal variant leading to decreased function. The HapB3 haplotype definition was also retained for cases where only the c.1236G>A variant is tested (e.g. whole exome sequencing). While CPIC recommends to directly test the causal SNP if possible, in cases where only c.1236G>A is tested or results are available for, it should be clearly stated in the test report that "decreased function" was inferred by detecting the exonic tag SNP, and disclose that in rare cases, the causal decreased function variant c.1129-5923C>G may not be present despite having this tag SNP.	\N	f
778330	377	DPYD	c.46C>G	Normal function	Normal function	\N	1.0	778329	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013740047, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778476	365	DPYD	c.2915A>G	Normal function	Normal function	\N	1.0	778475	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.00008924864, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.00922293}	f
778478	365	DPYD	c.2921A>T	Normal function	Normal function	\N	1.0	778477	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778480	365	DPYD	c.2933A>G	No function	No function	\N	0.0	778479	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778456	365	DPYD	c.2303C>A	Normal function	Normal function	\N	1.0	778455	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0018162305, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778458	365	DPYD	c.2336C>A	Normal function	Normal function	\N	1.0	778457	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013281931, "East Asian": 0.0010211836, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778460	365	DPYD	c.2482G>A	Normal function	Normal function	\N	1.0	778459	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0001131909, "East Asian": 0.0, "Central/South Asian": 0.000089115194, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778462	365	DPYD	c.2582A>G	Normal function	Normal function	\N	1.0	778461	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.00029061755, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778464	365	DPYD	c.2623A>C	Normal function	Normal function	\N	1.0	778463	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.00028225806, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778466	365	DPYD	c.2639G>T	No function	No function	\N	0.0	778465	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.00070, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778468	365	DPYD	c.2656C>T	Normal function	Normal function	\N	1.0	778467	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.00010, "European": 0.00036403185, "East Asian": 0.00010, "Central/South Asian": 0.001, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778470	365	DPYD	c.2657G>A (*9B)	Normal function	Normal function	\N	1.0	778469	{24648345}	Moderate	This rsID, when combined with rs1801265 makes up DPYD*9B	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013373986, "East Asian": 0.00032379513, "Central/South Asian": 0.00016493561, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778472	365	DPYD	c.2846A>T	Decreased function	Decreased function	\N	0.5	778471	{24648345}	Strong	\N	5-fluorouracil (in vitro)	{"Latino": 0.0020888615, "European": 0.0037400308, "East Asian": 0.0, "Central/South Asian": 0.000640429, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0031082802}	f
778474	365	DPYD	c.2872A>G	No function	No function	\N	0.0	778473	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.00001364737, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778715	336	G6PD	202G>A_376A>G_1264C>G	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778714	{18677765,22293322}	limited	\N	Function assigned based on the WHO recommendations and in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778753	336	G6PD	A	IV/Normal	IV/Normal	\N	\N	778752	{1303173,22293322,32387609,3446582}	moderate	\N	Although originally classified as a WHO class III/decreased function variant (3446582, 22293322), recent studies show that the catalytic activity and structural stability of G6PD A is similar to that of the WT enzyme (32387609, 1303173). Therefore, consensus among experts was IV/Normal function due to moderate evidence.	{"Latino": 0.014873203, "European": 0.00054859073, "East Asian": 0.0, "Central/South Asian": 0.0007337911, "African American/Afro-Caribbean": 0.3183956}	f
778703	336	G6PD	Amazonia	II/Deficient	II/Deficient	\N	\N	778702	{22293322,12367584}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778847	336	G6PD	Sugao	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778846	{22293322,11594515}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778983	336	G6PD	Sumare	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778982	{22293322,9298828}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
828096	229	MT-RNR1	Reference	\N	Normal risk of aminoglycoside-induced hearing loss	\N	\N	828095	{27654872}	\N	\N	27654872: N/A	\N	f
3827893	157	MT-RNR1	m.951G>A	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827892	{18830133,18851951}	Inadequate evidence	\N	MT-RNR1 951G>A is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. Screening of individuals with aminoglycoside-hearing loss identified this variant in two studies (18830133, 18851951). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.012948994, "East Asian": 0.003374, "Near Eastern": 0.0, "Central/South Asian": 0.0006698, "Sub-Saharan African": null}	f
3827905	157	MT-RNR1	m.1095T>C	\N	increased risk of aminoglycoside-induced hearing loss	\N	\N	3827904	{11079536,11313749,15555598,15841390,16875663,21205314}	Moderate	\N	MT-RNR1 1095T>C is assigned an increased risk of aminoglycoside-induced hearing loss based on moderate evidence. Screening of individuals or probands of individuals with aminoglycoside-hearing looss identified 1095T>C in a number of cases (11079536, 11313749, 15555598, 15841390, 16875663, 21205314). Therefore, consensus among experts was this variant is associated with increased risk of aminoglycoside-induced hearing loss based on moderate evidence.	{"European": 0.00057115, "East Asian": 0.001464755, "Near Eastern": 0.0, "Central/South Asian": 0.0006698, "Sub-Saharan African": 0.0}	f
779101	142	NUDT15	*19	\N	No function	\N	\N	779100	{30728528}	Limited	\N	NUDT15*19 is assigned no function based on limited evidence. One patient genotyped NUDT15*1/*19 received 150 mg of azathiopurine daily and experienced pancytopenia after 1 week of treatment. However, this patient was also heterozygous for an inactivating TPMT allele (30728528). Four out of seven variant effect predictors tested by CPIC staff predict that the NUDT15*19-defining SNV (c.3G>C (p.M1I)) impairs protein function. c.3G>C is predicted to disrupt protein translation due to the loss of the canonical start codon, and there is no alternative start codon available.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
779099	142	NUDT15	*18	\N	No function	\N	\N	779098	{30728528}	Limited	\N	NUDT15*18 is assigned no function based on limited evidence. One patient identified with the genotype NUDT15*1/*18 received 50 mg of 6-MP daily and experienced pancytopenia after 3 months of treatment. However, this patient was also heterozygous for an inactivating TPMT allele (30728528). NUDT15*18 is characterized by c.221delA, causing a frameshift (p.N74fs), that is predicted to impair protein function by CADD and PhD-SNP6. The deletion occurs in exon 2, which is within the Nudix hydrolase domain, and NUDT15*18 is predicted to produce a protein targeted for nonsense-mediated decay.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
3827895	157	MT-RNR1	m.960C>del	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827894	{18851951}	Inadequate evidence	\N	MT-RNR1 960C>del is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. Screening of individuals with aminoglycoside-hearing loss identified this variant in one study (18851951). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3827897	157	MT-RNR1	m.961T>G	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827896	{18830133}	Inadequate evidence	\N	MT-RNR1 961T<G is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. One report of normal hearing after aminoglycoside hearing loss in an invidual carrying this variant (18830133). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.0136944335, "East Asian": 0.0, "Near Eastern": 0.004947, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0}	f
3827899	157	MT-RNR1	m.961T>del	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827898	{15917167}	Inadequate evidence	\N	MT-RNR1 961T>del is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. In one study, 961T>del was detected in subjects in all four cohorts (no statistically significant difference in allele frequency between the groups). Pedigree analysis showed that T961del and the hearing loss phenotype did not co-segregate (15917167). Therefore, consensus among experts is that there is uncertain risk of aminoglycoside-induced hearing loss associated with this variant.	{"European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779073	364	NUDT15	*5	\N	Decreased function	\N	\N	779072	{26878724,28445187,28088792,28903549,32094170,32598049,32221476,33481917,34636169,39084859,33753169,36873097,33504140}	Moderate	27.7 Vmax/Km; *3/*5 patient has same intolerance to MP as *3/*3 patient	NUDT15*5 is assigned decreased function based on moderate evidence. Patients genotyped NUDT15*1/*5 or NUDT15*3/*5 exhibited increased dose-normalized levels of DNA-TG compared to patients genotyped NUDT15*1/*1 (33481917). Intermediate metabolizers, including those genotyped NUDT15*1/*5, have been shown to tolerate lower thiopurine doses (33481917, 32221476, 36873097, 33504140) and exhibit an increased risk of neutropenia (36873097). One patient genotyped NUDT15*3/*5 exhibited similar thiopurine intolerance to a patient genotyped NUDT15*3/*3 (26878724). In vitro studies using a bacterial expression system found that NUDT15.5 exhibits decreased enzymatic activity and decreased protein stability compared to NUDT15.1 (26878724, 33753169). However, published in silico analysis indicates that the NUDT15*5-defining SNV, c.52G>A (p.V18I) has minimal effect on protein structure and NUDT15.5 exhibits similar thermostability as NUDT15.1 (28088792). Despite these predictions, an experimentally derived crystal structure of NUDT15.5 found that c.52G>A (p.V18I) destabilizes the conserved NUDIX motif (33753169). Five out of nine variant effect predictors tested by CPIC staff predict that c.52G>A (p.V18I) impairs protein function. An additional in vitro study found that the NUDT15.5 protein is expressed at similar levels to NUDT15.1 and does not affect 6-MP sensitivity in HEK293 cells (32094176).	{"Latino": 0.0, "European": 0.000007794928, "East Asian": 0.01108, "Central/South Asian": 0.0004482}	f
779079	364	NUDT15	*8	\N	Decreased function	\N	\N	779078	{28659275,32094176}	Limited	\N	NUDT15*8 is assigned decreased function based on limited evidence. One patient genotyped NUDT15*2/*8 was extremely sensitive to thiopurine treatment (28659275). An in vitro study using a bacterial expression system found that NUDT15.8 exhibits decreased enzymatic activity and decreased protein thermostability compared to NUDT15.1 (28659275). An additional in vitro study expressed NUDT15*8 in HEK293 cells and found that protein expression and thiopurine sensitivity were comparable to cells expressing NUDT15*1 (32094176). Seven out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*8-defining SNV, c.103A>G (p.K35E), impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
779469	362	TPMT	*37	\N	No function	\N	\N	779468	{24710034,33118454}	Strong	\N	TPMT*37 is assigned no function based on strong evidence. Erythrocytes from individuals genotyped TPMT*1/*37 exhibited intermediate activity (24710034, 33118454). The TPMT*37-defining SNV, c.648T>A (p.C216X), results in the generation of a premature stop codon and the expression of a truncated protein. The premature stop variant occurs upstream of the known "no function" variant (c.719A>G, defining TPMT*3C), suggesting that loss of this region of the protein alters function. Three out of four variant effect predictors tested by CPIC staff predict that c.648T>A (p.C216X) impairs protein function.	{"Latino": 0.00008934, "European": 0.00003731825, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685589	175	RYR1	c.6961A>G	Benign	Normal function	\N	n/a	3685588	{35849058}	\N	\N	PM1, BS1, BS2, BS3_Sup	{"Latino": 0.00006545, "American": null, "European": 0.00091547164, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0002895}	f
3685313	175	RYR1	c.97A>G	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685312	{35849058}	\N	\N	PS2_PM6_Sup, PS4_Sup, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779151	363	RYR1	c.103T>C	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779150	{33767344}	\N	\N	PS4_Mod, PM1, PP1_St, PP3_Mod	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685317	175	RYR1	c.119G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685316	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685327	175	RYR1	c.178G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685326	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779149	229	RYR1	Reference	Benign	Normal function	\N	n/a	779148	{}	\N	\N	\N	\N	f
3685309	175	RYR1	c.38T>G	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685308	{35849058}	\N	\N	PS3_Mod, PS4_Mod, PM1, PP1	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685311	175	RYR1	c.51_53del	Variant of uncertain significance	Uncertain function	\N	n/a	3685310	{35849058}	\N	\N	PM1	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685643	175	RYR1	c.7291G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685642	{35849058}	\N	\N	PS4_Mod, PM1, PP3_Mod	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00004827}	f
3685645	175	RYR1	c.7291G>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685644	{35849058}	\N	\N	PS3_Mod, PS4_Mod, PM1_Sup, PM5_Sup, PP1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685647	175	RYR1	c.7292A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685646	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PM5_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779209	363	RYR1	c.7300G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779208	{33767344}	\N	\N	PS3, PS4, PM1, PP1_St, PP3_Mod, BS2	{"Latino": null, "American": null, "European": 0.00008819, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00004825}	f
779211	363	RYR1	c.7304G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779210	{33767344}	\N	\N	PS3_Mod, PS4, PM1, PP1_St, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685653	175	RYR1	c.7304G>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685652	{35849058}	\N	\N	PS4_Mod, PM1_Sup, PM5, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685655	175	RYR1	c.7307G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685654	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685629	175	RYR1	c.7099G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685628	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": 0.00006543, "American": null, "European": 0.00004411, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685631	175	RYR1	c.7112A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685630	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685633	175	RYR1	c.7123G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685632	{33767344}	\N	\N	PS4_Sup, PM1_Sup, PM5, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779205	363	RYR1	c.7124G>C	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779204	{33767344}	\N	\N	PS3_Mod, PS4_Mod, PM1, PP1_Mod, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685637	175	RYR1	c.7199A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685636	{35849058}	\N	\N	PM1	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00004831}	f
3685639	175	RYR1	c.7210G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685638	{35849058}	\N	\N	PM1, PP1	{"Latino": 0.00006544, "American": null, "European": 0.00001471, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000483}	f
779207	363	RYR1	c.7282G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	779206	{33767344}	\N	\N	PS3_Mod, PS4_Mod, PM1, PP3_Mod	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002413}	f
3685665	175	RYR1	c.7355G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685664	{35849058}	\N	\N	PM1_Sup, PM5_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779215	363	RYR1	c.7360C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779214	{33767344}	\N	\N	PS3_Mod, PS4_Mod, PM1_Sup, PM5, PP1, PP3_Mod	{"Latino": null, "American": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002413}	f
3685763	175	RYR1	c.9848G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685762	{35849058}	\N	\N	None	{"Latino": 0.00006545, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685767	175	RYR1	c.9868G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685766	{35849058}	\N	\N	None	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00002415}	f
3685859	175	RYR1	c.12689T>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685858	{35849058}	\N	\N	PS4_Mod, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685867	175	RYR1	c.12881C>T	Benign	Normal function	\N	n/a	3685866	{33767344}	\N	\N	BA1	{"Latino": 0.0009516, "American": null, "European": 0.0002127, "East Asian": null, "Near Eastern": 0.006452, "Central/South Asian": null, "Sub-Saharan African": 0.01471}	f
3685945	175	RYR1	c.14567C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685944	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685949	175	RYR1	c.14581C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685948	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PM5_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779243	363	RYR1	c.14582G>A	Variant of uncertain significance	Uncertain function	\N	n/a	779242	{33767344}	\N	\N	PS3_Mod, PS4_Sup, PM1_Sup, PP3_Mod, BS2	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685951	175	RYR1	c.14627A>G	Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685950	{35849058}	\N	\N	PS3_Mod, PS4_Mod, PM1_Sup, PP1_St, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685953	175	RYR1	c.14639T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685952	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685955	175	RYR1	c.14678G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685954	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685957	175	RYR1	c.14680G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685956	{35849058}	\N	\N	PS3_Mod, PM1_Sup, PP3_Mod	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779332	362	SLCO1B1	*28	\N	Uncertain function	\N	\N	779331	{22147369}	Inadequate	\N	SLCO1B1*28 is assigned uncertain function based on no in vitro evidence and limited clinical data. One clinical study showed no statistical difference in methotrexate clearance (22147369). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779280	363	SLCO1B1	*2	\N	Uncertain function	\N	\N	779279	{11477075,12490595}	Inadequate	\N	SLCO1B1*2 is assigned uncertain function based on in vitro studies demonstrating reduced uptake of estrone sulfate, estradiol 17beta-d-glucuronide and rifampin (11477075, 12490595), but no clinical data. Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779306	362	SLCO1B1	*15	Decreased function	No function	\N	\N	779305	{15970799,21245207,25350695,31220337}	Definitive	\N	SLCO1B1*15 is assigned no function based on strong evidence in heterozygous and homozygous patients, and in vitro studies. SLCO1B1*15 has been studied for more than 15 years and its association with impaired function compared to wildtype is well-established (21245207, 25350695, 31220337). Though in vitro, the *15 allele may have more function than the *5 allele, analyses of pharmacokinetics and statin-associated muscle symptoms are usually performed on the rs4149056 variant included in the *5 and *15 alleles, so the same functional status was assigned for each of these alleles.	{"American": 0.24, "European": 0.15017298, "Oceanian": 0.0, "East Asian": 0.12453574, "Near Eastern": 0.15, "Central/South Asian": 0.065170676, "Sub-Saharan African": 0.027934482, "African American/Afro-Caribbean": 0.01}	f
779340	362	SLCO1B1	*32	\N	Uncertain function	\N	\N	779339	{22147369}	Inadequate	\N	SLCO1B1*32 is assigned uncertain function based on no in vitro evidence and limited clinical data. One clinical study showed no statistical difference in methotrexate clearance for one heterozygous patient (22147369). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779401	362	TPMT	*3C	\N	No function	\N	\N	779400	{16220112,18708949,8644731,8561894,9177237,9246020,9931346,15226673,23252716,23585236,29387964,33928426,33568932,31005613,15255798,33205673,19057372,14508387,9695718,14656901,9103127,24322830,11304783,19048245,11372592,18021342,15167635,9711875,16952345,9831928,10997970,14985890}	Definitive	\N	TPMT*3C is assigned no function based on definitive evidence. Erythrocytes from individuals heterozygous for TPMT*3C exhibited intermediate enzymatic activity, while erythrocytes from individuals homozygous for TPMT*3C or heterozygous for TPMT*3C in combination with another no function allele exhibited low enzymatic activity (9246020, 9931346, 15226673, 23252716, 31005613, 15255798, 14508387, 9695718, 14656901, 9103127, 24322830, 19048245, 11372592, 18021342, 15167635, 9711875, 16952345, 9831928, 10997970, 14985890). Patients carrying TPMT*3C alleles exhibited increased plasma concentrations of TGNs, increased DNA-incorporated thioguanine, decreased plasma concentrations of methylated metabolites, and tolerated lower doses of thiopurines (11304783, 19057372, 33568932, 33205673, 33928426, 29387964, 23585236). In vitro studies demonstrate that TPMT.3C exhibited decreased protein expression, decreased protein stability, and enzymatic activity was decreased by 50-80% relative to TPMT.1 in yeast cells (9177237, 8644731), mammalian cells (16220112, 18708949, 8561894), and patient erythrocytes (9695718). TPMT.3C decreased protein expression is attributed to rapid degradation by the proteasome (16220112). Eight out of ten variant effect predictors tested by CPIC staff predict that the TPMT*3C-defining SNV, c.719A>G (p.Y240C), impairs protein function.	{"Latino": 0.005828808, "European": 0.0049218307, "East Asian": 0.01636903, "Near Eastern": 0.009404483, "Central/South Asian": 0.011216759, "Sub-Saharan African": 0.052884888, "African American/Afro-Caribbean": 0.024}	f
779471	362	TPMT	*38	\N	No function	\N	\N	779470	{25564374}	Limited	\N	TPMT*38 is assigned no function based on limited evidence. Two patients were genotyped TPMT*1/*38. One patient with ALL received 26.9-53.8 mg/m2 mercaptopurine, which is 36-72% of the standard dose. The other patient exhibited intermediate TPMT enzymatic activity (25564374). Four out of ten variant effect predictors tested by CPIC staff predict that the TPMT*38-defining SNV, c.514T>C (p.S172P), impairs protein function.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0004059, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779501	362	UGT1A1	*80	\N	Unknown function	\N	\N	779500	{}	\N	UGT1A1*80 is in very high linkage disequilibrium with *28 and *37. However, the function of the *80 allele alone, in the absence of *28 or *37, is uncertain. If a patient is only tested for *80, decreased function may be inferred.	\N	{"Latino": 0.3827317, "European": 0.31424528, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.4503211}	f
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