3685689	190	RYR1	c.7528T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685688	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685727	190	RYR1	c.8518C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685726	{35849058}	\N	\N	None	{"Latino": null, "European": 0.0000161, "East Asian": 0.0000892, "Near Eastern": null, "Central/South Asian": 0.0002307, "Sub-Saharan African": null}	f
3685751	190	RYR1	c.9635A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685750	{35849058}	\N	\N	None	{"Latino": 0.0001141, "European": 0.0004267648, "East Asian": null, "Near Eastern": 0.000057640038, "Central/South Asian": null, "Sub-Saharan African": 0.0000679}	f
3685893	190	RYR1	c.14002C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685892	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "European": 0.000008041874, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685915	190	RYR1	c.14422_14423delinsAA	Variant of uncertain significance	Uncertain function	\N	n/a	3685914	{35849058}	\N	\N	PM1_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685977	190	RYR1	c.14918C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685976	{}	\N	Reference: MHS VCEP	PS3_Mod, PS4_Strong, PM1_Sup, PP1, PP3_Mod (Codes, https://erepo.clinicalgenome.org/evrepo/ui/classification/8e77a22f-9abe-497a-adde-e81a860e9060)	{"Latino": 0.000050, "European": 0.0000297, "East Asian": 0.0000223, "Near Eastern": null, "Central/South Asian": 0.000022, "Sub-Saharan African": 0.0000134}	f
779342	377	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
777689	399	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
777799	381	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
778973	351	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
778809	351	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
3685859	190	RYR1	c.12689T>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685858	{35849058}	\N	\N	PS4_Mod, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779431	377	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
779435	377	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
778019	395	CYP2D6	*43	\N	Uncertain function	\N	n/a	778018	{24647041,30366777}	Inadequate	\N	CYP2D6*43 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*43 demonstrated enzyme activity ranging from nondetectable to similar activity compared to wildtype with various substrates (24647041, 30366777). Therefore, consensus among experts was uncertain function.	{"Latino": null, "American": 0.0, "European": 0.00058934913, "Oceanian": 0.002, "East Asian": 0.00038300423, "Near Eastern": 0.003, "Central/South Asian": 0.01, "Sub-Saharan African": 0.0100665875, "African American/Afro-Caribbean": 0.006397251}	f
778201	301	CYP2D6	*141	\N	Uncertain function	\N	n/a	778200	{}	Inadequate	\N	CYP2D6*141 is assigned uncertain function due to the presence of variants found in other alleles known to cause decreased (*17) or no function (*36); there is no literature describing the combined effect of the variants found in this allele. 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
2091245	299	CYP2D6	*156	\N	No function	\N	0.0	2091244	{}	Limited	\N	CYP2D6*156 is assigned no function based on limited evidence. CYP2D6*156 is defined by the five SNPs defining the decreased function *29 allele and one additional SNP, 154C>T which causes a premature stop codon (Q52X) that likely renders the allele nonfunctional. 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": 0.00104, "African American/Afro-Caribbean": null}	f
778961	351	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	351	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	351	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
3685867	190	RYR1	c.12881C>T	Benign	Normal function	\N	n/a	3685866	{33767344}	\N	\N	BA1	{"Latino": 0.000863, "European": 0.0001063, "East Asian": null, "Near Eastern": 0.0020408, "Central/South Asian": null, "Sub-Saharan African": 0.0155997}	f
3685945	190	RYR1	c.14567C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685944	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777541	399	CYP2C19	*5	\N	No function	\N	\N	777540	{9103550,10022751,21325430,25001882,21692664}	Moderate	\N	CYP2C19*5 is assigned no function based on moderate evidence in heterozygous subjects and in vitro studies. CYP2C19*5 was first described in a subject demonstrating decreased mephenytoin metabolism compared to wildtype subjects and similar mephenytoin metabolism compared to CYP2C19 *2/*2, CYP2C19 *2/*3, and CYP2C19 *3/*3 subjects based on S/R mephenytoin ratio in urine metabolites (9103550) . One CYP2C19*2/*5 subject similarly demonstrated decreased phenytoin metabolism based on S/R mephenytoin ratio in urine metabolites. This result was correlated with an in vitro study which showed CYP2C19*5 had a 40% decrease in enzyme expression, 0.4% enzyme activity with a mephenytoin substrate, and nondetectable enzyme activity with a tolbutamide substrate compared to wildtype (10022751). Two additional in vitro studies using different cell systems found CYP2C19*5 had nondetectable enzyme activity with mephenytoin, omeprazole, and clopidogrel substrates (21325430, 25001882). CYP2C19.5B showed no activity towards CEC (3-cyano-7-ethoxycoumarin) O-deethylation (21692664). Therefore, consensus among experts was no function based on moderate evidence.	{"Latino": 0.0, "American": 0.0, "European": 0.000028767667, "Oceanian": null, "East Asian": 0.0032252397, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777805	381	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
777987	395	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
778071	395	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
778141	394	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
3318602	142	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
778963	351	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
778923	351	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
778362	386	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	190	RYR1	c.8654C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685734	{35849058}	\N	\N	None	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779499	377	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
777563	399	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
778791	351	G6PD	Miaoli	II/Deficient	II/Deficient	\N	\N	778790	{22293322,9444913}	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
778977	351	G6PD	Tokyo, Fukushima	I-II/Deficient with CNSHA-Deficient	I/Deficient with CNSHA	\N	\N	778976	{22293322,28028996,7440223,9192788,1733837}	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
3685889	190	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, "European": 0.000003419, "East Asian": null, "Near Eastern": 0.0001036, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685909	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685931	190	RYR1	c.14510delA	Likely Benign	Normal function	\N	n/a	3685930	{35849058}	\N	\N	PS4_Sup, BS2_Mod, BS3_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779239	378	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685949	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
1002698	371	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	377	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
779495	378	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
777789	399	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
778009	395	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
778817	351	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
779005	351	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
779334	377	SLCO1B1	*29	\N	Uncertain function	\N	\N	779333	{22147369,33658230}	Inadequate	\N	SLCO1B1*29 is assigned uncertain function based on limited in vitro evidence and limited 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": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
7726085	17	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
779489	379	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
779481	157	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
778689	351	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
779243	378	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779316	377	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
777591	399	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
777775	399	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
1777307	300	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
778005	395	CYP2D6	*36	\N	No function	\N	0.0	778004	{7935325,18784265,9918137,16425111,24647041,30366777,16415111}	Moderate	\N	CYP2D6*36 is assigned no function based on moderate evidence in heterozygous subjects and in vitro studies. CYP2D6*36 has been described in subjects with CYP2D6 *1/*36 and CYP2D6 *2/*36 genotype demonstrating decreased metabolism and subjects with CYP2D6 *4/*36 demonstrating poor metabolism with debrisoquine and dextromethorphan substrates (9918137, 16415111). Multiple in vitro studies found CYP2D6*36 had nondetectable or markedly decreased enzyme activity compared to wildtype with various substrates (7935325, 18784265, 24647041, 30366777). Therefore, consensus among experts was no function with an activity value of 0 based on moderate evidence.	{"Latino": 0.002, "American": 0.0, "European": 0.00017518068, "Oceanian": 0.0, "East Asian": 0.011395853, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.004, "African American/Afro-Caribbean": 0.005231697}	f
3827887	172	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
778921	351	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
778669	351	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
7726087	17	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
5881977	56	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
779699	326	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
777997	395	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
779007	351	G6PD	Amiens	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	779006	{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
778777	351	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
779097	157	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
3685777	190	RYR1	c.10229C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685776	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685885	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779304	378	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
777483	399	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
777783	399	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
777993	395	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
778049	394	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	394	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
779009	351	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
778783	351	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
1002690	371	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
777787	399	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
1406318	381	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
777961	395	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
778057	395	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
778205	301	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
3685619	190	RYR1	c.7084G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685618	{35849058}	\N	\N	PS4_Mod, PM1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685623	190	RYR1	c.7089C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685622	{35849058}	\N	\N	PS4_Mod, PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779213	378	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685731	190	RYR1	c.8600T>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685730	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685781	190	RYR1	c.10252A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685780	{35849058}	\N	\N	PS4_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685725	190	RYR1	c.8360C>G	Benign	Normal function	\N	n/a	3685724	{35849058}	\N	\N	BA1	{"Latino": 0.0028406, "European": 0.0002637, "East Asian": null, "Near Eastern": 0.008928544, "Central/South Asian": 0.0001875, "Sub-Saharan African": 0.029597}	f
779322	378	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
778043	395	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
778069	395	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
778163	394	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	351	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	351	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
778941	351	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
778807	351	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
3685883	190	RYR1	c.13913G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685882	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778755	351	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
778745	351	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
3685895	190	RYR1	c.14051T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685894	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685937	190	RYR1	c.14524G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685936	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": 0.0000167, "European": 0.0000576, "East Asian": 0.0000668, "Near Eastern": 0.0007565283, "Central/South Asian": 0.0001098, "Sub-Saharan African": 0.0003337}	f
3685981	190	RYR1	c.15059G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685980	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
1357094	360	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
778115	395	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
778737	351	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	351	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
3685435	190	RYR1	c.1597C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685434	{33767344}	\N	\N	PM1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3827909	172	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
3685429	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685965	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685515	190	RYR1	c.5317C>T	Benign	Normal function	\N	n/a	3685514	{33767344}	\N	\N	BA1	{"Latino": 0.0000167, "European": 0.0000136, "East Asian": 0.0151313, "Near Eastern": null, "Central/South Asian": 0.0001208, "Sub-Saharan African": null}	f
778967	351	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	351	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
778835	351	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
3685973	190	RYR1	c.14825G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685972	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685975	190	RYR1	c.14879T>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685974	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3827889	172	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
2784573	171	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	171	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
779075	379	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
3685541	190	RYR1	c.6388G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685540	{35849058}	\N	\N	PM1, PP3_Mod	{"Latino": null, "European": 0.000008474, "East Asian": 0.0000446, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000134}	f
3685555	190	RYR1	c.6544A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685554	{35849058}	\N	\N	PS4_Sup, PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685679	190	RYR1	c.7385C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685678	{33767344}	\N	\N	PP3_Mod	{"Latino": 0.000050, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.000022, "Sub-Saharan African": 0.0000133}	f
779225	378	RYR1	c.7522C>G	Variant of uncertain significance	Uncertain function	\N	n/a	779224	{}	\N	Reference: MHS VCEP	PS3_Mod, PM5_Sup (Codes; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/366bdce7-ddad-4b5f-a185-f7b8021f1831)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685701	190	RYR1	c.7787C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685700	{35849058}	\N	\N	None	{"Latino": 0.0001002, "European": 0.000003391, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779314	377	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	377	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
1002706	371	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
777709	399	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
777727	399	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
779083	157	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
779095	157	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	190	RYR1	c.11314C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685804	{33767344}	\N	\N	PS4_Sup, PM5_Sup, PP3_Mod	{"Latino": 0.0000167, "European": 0.00000678, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685803	190	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, "European": 0.000002543, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.000022, "Sub-Saharan African": 0.0000267}	f
3685829	190	RYR1	c.12028G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685828	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "European": 0.000041777836, "East Asian": 0.0000223, "Near Eastern": null, "Central/South Asian": 0.000011, "Sub-Saharan African": 0.0000668}	f
3685891	190	RYR1	c.13994_13995delTCinsCT	Variant of uncertain significance	Uncertain function	\N	n/a	3685890	{35849058}	\N	\N	PS2_PM6_Sup, PM1_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779409	377	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
777739	399	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
778223	392	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	391	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
778231	392	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
778235	391	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
778219	392	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
779205	378	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685637	190	RYR1	c.7199A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685636	{35849058}	\N	\N	PM1	{"Latino": null, "European": 0.0000153, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000267}	f
779510	209	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	209	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
777441	399	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
777461	399	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
777545	399	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
779069	379	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
3685639	190	RYR1	c.7210G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685638	{35849058}	\N	\N	PM1, PP1	{"Latino": 0.0000334, "European": 0.0000136, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.000055, "Sub-Saharan African": 0.0000535}	f
779451	377	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
779479	157	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
777681	399	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
777669	398	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
778123	394	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
3685469	190	RYR1	c.3095G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685468	{35849058}	\N	\N	None	{"Latino": null, "European": 0.0002792, "East Asian": null, "Near Eastern": 0.0003384, "Central/South Asian": 0.0000332, "Sub-Saharan African": 0.0000267}	f
3685471	190	RYR1	c.3127C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685470	{35849058}	\N	\N	PP3_Mod	{"Latino": 0.0000528, "European": 0.0000056844806, "East Asian": null, "Near Eastern": 0.0000343, "Central/South Asian": 0.0000113, "Sub-Saharan African": 0.0000135}	f
3685757	190	RYR1	c.9676G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685756	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779455	377	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
779465	377	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
779457	377	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
1103382	301	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	299	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	299	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
778330	392	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
778332	392	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	392	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	386	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	386	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
778753	351	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	351	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	351	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	351	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
3827905	172	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
779207	378	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, "European": 0.0000136, "East Asian": null, "Near Eastern": 0.0001644, "Central/South Asian": 0.000022, "Sub-Saharan African": 0.0000133}	f
3685643	190	RYR1	c.7291G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685642	{35849058}	\N	\N	PS4_Mod, PM1, PP3_Mod	{"Latino": null, "European": 0.000011236715, "East Asian": 0.0000223, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000267}	f
3827897	172	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
779099	157	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
779101	157	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
3685309	190	RYR1	c.38T>G	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685308	{35849058}	\N	\N	PS3_Mod, PS4_Mod, PM1, PP1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779151	378	RYR1	c.103T>C	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779150	{33767344}	\N	\N	PS4_Mod, PM1, PP1_St, PP3_Mod	{"Latino": null, "European": 0.000002545, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685311	190	RYR1	c.51_53del	Variant of uncertain significance	Uncertain function	\N	n/a	3685310	{35849058}	\N	\N	PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685313	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685317	190	RYR1	c.119G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685316	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685327	190	RYR1	c.178G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685326	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685589	190	RYR1	c.6961A>G	Benign	Normal function	\N	n/a	3685588	{35849058}	\N	\N	PM1, BS1, BS2, BS3_Sup	{"Latino": 0.0002332, "European": 0.0014453047, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0003198}	f
3685629	190	RYR1	c.7099G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685628	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": 0.0001001, "European": 0.0000441, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.000011, "Sub-Saharan African": null}	f
3685631	190	RYR1	c.7112A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685630	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779469	377	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
777265	399	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
777427	399	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
778797	351	G6PD	Malaga	III/Deficient	III/Deficient	\N	\N	778796	{22293322,8956035,22963789}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.00028541868, "European": 0.00001806179, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0011595425}	f
778987	351	G6PD	Pawnee	II/Deficient	II/Deficient	\N	\N	778986	{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
3685953	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685957	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779332	377	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
779401	377	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
779501	377	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
778813	351	G6PD	Sibari	III/Deficient	III/Deficient	\N	\N	778812	{22293322,8447319}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.000010243173, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.000036485697}	f
3685951	190	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, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685955	190	RYR1	c.14678G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685954	{35849058}	\N	\N	PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777469	398	CYP2B6	*25	\N	Uncertain function	\N	\N	777468	{20517174,21746968,30201214}	Inadequate	\N	CYP2B6*25 (c.1454A>T, p.Q485L) – Uncertain function: CYP2B6*25 is assigned uncertain function. In vitro studies using cDNA expression systems showed no significant changes in enzyme activity and/or protein expression compared to the *1 reference (20517174, 21746968, 30201214). However, there were no in vivo data available or data in human liver microsomes. Therefore, consensus among experts was uncertain function based on inadequate 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
777941	395	CYP2D6	*3	\N	No function	\N	0.0	777940	{2211621}	Limited	\N	CYP2D6*3 is assigned no function based on limited evidence. CYP2D6*3 was first described in a heterozygous subject demonstrating decreased sparteine metabolism based on an elevated urinary metabolite ratio. CYP2D6*3 is defined by a single nucleotide deletion causing a frameshift and resulting in a nonfunctional protein (2211621). 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": 0.0071793622, "American": 0.000654978, "European": 0.015922716, "Oceanian": 0.0010404624, "East Asian": 0.0000556167, "Near Eastern": 0.0043491097, "Central/South Asian": 0.0012986185, "Sub-Saharan African": 0.0009698735, "African American/Afro-Caribbean": 0.0032821998}	f
778045	395	CYP2D6	*56	\N	No function	\N	0.0	778044	{16679388,17392730}	Limited	\N	CYP2D6*56 is assigned no function based on limited evidence. A subject with CYP2D6 *4/*56 genotype demonstrated poor dextromethorphan metabolism based on urine metabolites on multiple occasions (17392730). CYP2D6*56 was identified in an hepatocyte demonstrating undetectable CYP2D6 protein expression and undetectable enzyme activity with dextromethorphan and bufuralol substrates (16679388). CYP2D6*56 is defined by a premature 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": 0.0, "European": 0.0008093927, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.002, "African American/Afro-Caribbean": 0.0015748427}	f
778065	395	CYP2D6	*68	\N	No function	\N	0.0	778064	{22111604}	Limited	\N	CYP2D6*68 is assigned no function based on limited evidence. CYP2D6*68 is a CYP2D6-CYP2D7 hybrid gene similar to CYP2D6*4 which results in a nonfunctional protein (22111604). Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": 0.001, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.001, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778073	395	CYP2D6	*72	\N	Uncertain function	\N	n/a	778072	{19158312,24647041,30366777}	Inadequate	\N	CYP2D6*72 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*72 demonstrated decreased enzyme activity compared to wildtype with various substrates (19158312, 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": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778081	395	CYP2D6	*81	\N	No function	\N	0.0	778080	{23799451}	Limited	\N	CYP2D6*81 is assigned no function based on limited evidence. CYP2D6*81 was identified in a subject demonstrating impaired enzyme activity based on experiencing adverse effects with venlafaxine and subsequently elevated nortriptyline levels (23799451). CYP2D6*81 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
778131	395	CYP2D6	*106	\N	Uncertain function	\N	n/a	778130	{26937359,23897164}	Inadequate	\N	CYP2D6*106 is assigned uncertain function due to inadequate evidence. CYP2D6*106 is defined by a single SNP which in silico studies predict to be a benign amino acid change (26937359). An in vitro study found CYP2D6*106 demonstrated decreased enzyme activity compared to wildtype with bufuralol and dextromethorphan substrates (23897164). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": 0.001, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.015, "African American/Afro-Caribbean": 0.0}	f
778191	394	CYP2D6	*136	\N	Uncertain function	\N	n/a	778190	{32759992}	Inadequate	\N	CYP2D6*136 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 8.9% and 12.7% compared to *1 for tamoxifen N-desmethylation and dextromethorphan O-demethylation, respectively (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
778203	301	CYP2D6	*142	\N	Uncertain function	\N	n/a	778202	{33998274}	Inadequate	\N	CYP2D6*142 is assigned uncertain function based on inadequate evidence. A subject sequenced as CYP2D6*10/*142 had a risperidone/9-hydroxy-risperidone ratio comparable to subjects with an AS of 0.25, 0.5 or 0.75 (33998274). CYP2D6*142 is a rare allele defined by several SNPs including 100C>T which causes decreased function in other CYP2D6 alleles (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
777593	399	CYP2C19	*34	\N	Uncertain function	\N	\N	777592	{23799451}	Inadequate	\N	CYP2C19*34 is assigned uncertain function due to inadequate evidence. CYP2C19*34 was identified in a patient heterozygous for the CYP2C19*2 allele who experienced adverse effects with venlafaxine and a supratherapeutic nortriptyline level. CYP2C19 enzyme function was not adequately assessed as CYP2D6 is involved in metabolism of antidepressants such as nortriptyline and this patient was a CYP2D6 intermediate metabolizer (23799451). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"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
777537	399	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
777539	399	CYP2C19	*4	\N	No function	\N	\N	777538	{9435198,21358751}	Limited	\N	CYP2C19*4 is assigned no function based on limited evidence in heterozygous subjects and an in vitro study. Two subjects with CYP2C19 *2/*4 genotype demonstrated decreased mephenytoin metabolism compared to wildtype subjects based on urine metabolite concentrations. This correlated with the in vitro experiment which found CYP2C19*4 protein was not expressed but mRNA levels were similar to wildtype indicating CYP2C19*4, which is defined by a SNP in the initiation codon, is not properly translated (9435198). Thus, the CYP2C19*4 defining SNP would result in a nonfunctional protein, even in the presence of a SNP associated with increased enzyme function (21358751). 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": 0.0005202914, "American": 0.00001870861, "European": 0.002359747, "Oceanian": null, "East Asian": 0.00017735043, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777543	399	CYP2C19	*6	\N	No function	\N	\N	777542	{9732415,21325430,25001882}	Limited	\N	CYP2C19*6 is assigned no function based on limited evidence in a heterozygous subject and in vitro studies. CYP2C19*6 was first described in a subject demonstrating decreased mephenytoin metabolism based on urine metabolite concentrations. This correlated with an in vitro study which found CYP2C19*6 had nondetectable enzyme activity with mephenytoin and tolbutamide substrates (9732415). Two additional in vitro studies using different cell systems found CYP2C19*6 had nondetectable enzyme activity with mephenytoin, omeprazole, and clopidogrel substrates (21325430, 25001882). 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": 0.00030023712, "Oceanian": null, "East Asian": 0.0005600443, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777707	399	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
777671	399	CYP2C9	*2	Decreased function	Decreased function	\N	0.5	777670	{29283396,20150829,1563752,12742136,10413320,27179628,25775139,19082874,30088221,15637526}	Definitive	\N	CYP2C9*2 is assigned decreased function based on definitive evidence in homozygous and heterozygous patients and in vitro experimental data. CYP2C9*2 has been studied for more than 20 years and its association with impaired function compared to wildtype is well-established (29283396, 20150829, 15637526). The phenotype for patients homozygous for the CYP2C9*2 variant was updated from poor metabolizer to intermediate metabolizer after reevaluation of prior and new evidence demonstrating CYP2C9*2 has more enzyme activity than CYP2C9*3, which results in in a similar phenotype for CYP2C9*1/*3 and CYP2C9 *2/*2 patients (12742136, 10413320, 27179628, 25775139, 19082874, 30088221), both of which can be distinguished from those homozygous for CYP2C9*3/*3. Therefore, consensus among experts was decreased function with an activity value of 0.5 based on definitive evidence.	{"Latino": 0.07625658, "American": 0.033402413, "European": 0.1273007, "Oceanian": 0.029310955, "East Asian": 0.0021256818, "Near Eastern": 0.12977302, "Central/South Asian": 0.11379695, "Sub-Saharan African": 0.013114594, "African American/Afro-Caribbean": 0.02243724}	f
778831	351	G6PD	Durham	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778830	{22293322,9290617}	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
778997	351	G6PD	Hermoupolis	II/Deficient	II/Deficient	\N	\N	778996	{22293322,10782016}	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
778843	351	G6PD	Lille	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778842	{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
778879	351	G6PD	Ludhiana	II/Deficient	II/Deficient	\N	\N	778878	{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	351	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
778887	351	G6PD	Rehevot	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778886	{22293322,11112389}	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
778683	351	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
3564277	202	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
778929	351	G6PD	Tomah	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778928	{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
778765	351	G6PD	Valladolid	II/Deficient	II/Deficient	\N	\N	778764	{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
778893	351	G6PD	Villeurbanne	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778892	{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
8101127	2	CYP3A5	*10	\N	\N	\N	\N	8101126	\N	\N	\N	\N	\N	f
8101129	2	CYP3A5	*11	\N	\N	\N	\N	8101128	\N	\N	\N	\N	\N	f
777943	395	CYP2D6	*4	\N	No function	\N	0.0	777942	{2211621,11266079,1978251,1978565}	Strong	\N	CYP2D6*4 is assigned no function based on strong evidence. CYP2D6*4 has consistently been described in subjects demonstrating decreased metabolism of various CYP2D6 substrates (2211621, 11266079, 1978251, 1978565). Two in vitro studies found CYP2D6*4 had undetectable protein expression (2211621, 11266079). CYP2D6*4 is defined by a splicing defect resulting in a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on strong evidence.	{"Latino": 0.12051356, "American": 0.10194215, "European": 0.1848476, "Oceanian": 0.017797798, "East Asian": 0.005269325, "Near Eastern": 0.11405941, "Central/South Asian": 0.089567736, "Sub-Saharan African": 0.028676093, "African American/Afro-Caribbean": 0.048111428}	f
779712	326	CYP2D6	*17x2	\N	Normal function	\N	1.0	777966	{8764380,8971426,11823760}	Limited	\N	CYP2D6*17x2 is assigned normal function based on limited evidence. CYP2D6*17 is assigned decreased function based on subjects demonstrating decreased enzyme activity with various substrates (8764380, 8971426, 11823760). Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence as it was determined the phenotypes containing a duplication of this allele would demonstrate greater enzyme activity than that of the nonduplicated allele and be clinically similar to phenotypes comprising normal function alleles.	{"Latino": 0.008826584, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.002, "African American/Afro-Caribbean": 0.0019977347}	f
5294109	92	CYP2D6	*27x2	\N	Increased function	\N	2.0	777986	{18784265,18838503,24647041,30366777}	Limited	\N	CYP2D6*27x2 was deposited into PharmVar. 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. Based on other normal function alleles such as *1, *2, *45, a duplication of a normal function allele is assigned an activity value of 2 and increased 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
778039	395	CYP2D6	*53	\N	Normal function	\N	1.0	778038	{18784265,24647041,30366777}	Limited	\N	CYP2D6*53 is assigned normal function based on limited evidence. Multiple in vitro studies found CYP2D6*53 had similar enzyme activity compared to wildtype with multiple substrates (18784265, 24647041). Although one in vitro study found CYP2D6*53 demonstrated decreased clearance compared to wildtype with a primaquine substrate (30366777) the experts did not find this result convincing as CYP2D6*53 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": 0.005, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00019958949, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
778189	394	CYP2D6	*135	\N	Uncertain function	\N	n/a	778188	{32759992}	Inadequate	\N	CYP2D6*135 is assigned uncertain function due to inadequate literature describing function of this allele. One in vitro study demonstrated decreased intrinsic clearance CLint (Vmax/Km) of 32.3% and 45.8% compared to *1 for tamoxifen N-desmethylation and dextromethorphan O-demethylation, respectively (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
1103378	301	CYP2D6	*146	\N	Uncertain function	\N	n/a	1103377	{}	Inadequate	\N	CYP2D6*146 is assigned uncertain function. CYP2D6*146 is defined by three SNPs all of which have been found in other star alleles; none of these SNPs have been implicated to cause no function; two are the defining SNPs of the normal function *2 allele and one is the defining SNP of uncertain function *43 allele. 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
2091257	299	CYP2D6	*162	\N	Uncertain function	\N	n/a	2091256	{}	Inadequate	\N	CYP2D6*162 is assigned uncertain function based on inadequate evidence. CYP2D6*162 is defined by the two SNPs defining the normal function *2 allele and the SNP defining the normal function *27 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
8102727	4	RYR1	c.1390C>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	8102726	{}	\N	Reference: MHS VCEP	PS3_Mod, PS4_Sup, PM1, PP1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
8102807	4	RYR1	c.4055C>G	Benign	Normal function	\N	n/a	8102806	{}	\N	Reference: MHS VCEP	BA1 (Codes, https://erepo.clinicalgenome.org/evrepo/ui/interpretation/835d1c5f-b870-498f-9389-ecbe96d31c9d)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
8102821	4	RYR1	c.4999C>T	Benign	Normal function	\N	n/a	8102820	{}	\N	Reference: MHS VCEP	BA1 (Codes, https://erepo.clinicalgenome.org/evrepo/ui/classification/3b67716e-0df3-49da-be62-066d465873c5)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
8103069	4	RYR1	c.9353C>T	Benign	Normal function	\N	n/a	8103068	{}	\N	Reference: MHS VCEP	BA1 (Codes, https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ff550456-5053-40d7-86de-84e32f5b1636)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3827885	172	MT-RNR1	m.827A>G	\N	normal risk of aminoglycoside-induced hearing loss	\N	\N	3827884	{16782057,18261986,18830133,20353758}	Limited	\N	MT-RNR1 827A>G is assigned a normal risk of aminoglycoside-induced hearing loss based on limited evidence. There are weak evidence proposing an association with aminoglycoside-induced hearing loss (16782057, 18261986, 20353758). However, there is one study showing patients with 827A>G mutation with a history of exposure to aminoglycosides with normal hearing (18830133) and this variant has too high a population frequency in certain haplogroups to be classified as associated with aminoglycoside-induced hearing loss. Therefore, consensus among experts was this variant is associated with normal risk of aminoglycoside-induced hearing loss based on limited evidence.	{"European": 0.0017502992, "East Asian": 0.035319928, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0}	f
7094209	44	MT-RNR1	m.930G>A	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	7094208	{18830133}	Inadequate evidence	\N	MT-RNR1 930G>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 one study (18830133). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence. While PMID 18830133 states that "..., 11 of the 151 sequences demonstrated an A > G transition at base position 930. Two of these patients had moderate-to-severe hearing loss." Table 3 of the article shows the G allele as the Human consensus and the 11 subjects as having the A allele. Furthermore, the guideline authors have reviewed institutional sample data and confirmed that the G allele is the reference allele. Therefore the variant is referenced as m.930G>A as of October 2025.	{"European": 0.0432228, "East Asian": 0.004054, "Near Eastern": 0.03408011, "Central/South Asian": 0.007368, "Sub-Saharan African": null}	f
3827893	172	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
3827895	172	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
3827899	172	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
8101106	2	CYP2D6	*186	\N	\N	\N	\N	8101105	\N	\N	\N	\N	\N	f
779071	379	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
2899163	188	CYP2B6	*49	\N	Uncertain function	\N	\N	2899162	{38596098}	Inadequate	\N	CYP2B6*49 (c.1301G>A, p.R434Q) – Uncertain function: CYP2B6*49 is assigned uncertain function due to inadequate evidence describing function. A single in vitro study reported decreased function for p.R434Q using buproprion and efavirez as probes (38596098).	{"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
779280	378	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
779294	378	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
8102297	2	NUDT15	*22	\N	\N	\N	\N	8102296	\N	\N	\N	\N	\N	f
8102299	2	NUDT15	*23	\N	\N	\N	\N	8102298	\N	\N	\N	\N	\N	f
779419	377	TPMT	*12	\N	Uncertain function	\N	\N	779418	{18708949,13679074,27564568,16220112,29785012}	Inadequate	\N	TPMT*12 is assigned uncertain function based on inadequate evidence. Patients genotyped TPMT*1/*12 exhibited TPMT enzymatic activity that is comparable to TPMT*1/*1 patients and there was no difference in 6-MP dose intensity between TPMT*1/*12 and TPMT*1/*1 patients (27564568). In vitro studies using mammalian cell expression systems found that TPMT.12 protein expression is decreased, enzymatic activity is decreased >50%, and TPMT.12 exhibited decreased affinity for 6-TG and SAM compared to TPMT.1 (16220112, 18708949). TPMT.12 also exhibited an increased rate of protein degradation compared to TPMT.1 (16220112). TPMT.12 enzymatic activity is decreased by 75% compared to TPMT.1 in yeast cells (13679074). An additional in vitro study found that TPMT.12 protein abundance in mammalian cells was comparable to TPMT.1 (29785012). Four out of ten variant effect predictors tested by CPIC staff predict that the TPMT*12-defining SNV, c.374C>T (p.S125L), impairs protein function.	{"Latino": 0.00008733, "European": null, "East Asian": 0.0000531, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
777267	399	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
777433	399	CYP2B6	*6	Decreased function	Decreased function	\N	\N	777432	{12642465,14551287,15194512,16338275,17178267,17235330,17329992,17559344,18171905,21659470,22232427,23080225,23344581,23550066,24260284,25456329,25565674,26389554,26655325,27799204,28723731,29756345,30201214,32238417,32302325,34752647,35538637}	Strong	\N	CYP2B6*6 (c.516G>T, p.Q172H/splice defect and c.785A>G, p.K262R) - Decreased function: CYP2B6*6 is assigned decreased function based on in vivo (homozygous and heterozygous patients) and in vitro studies. Significantly lower protein expression and activity was found in human liver microsomes, and increased plasma exposure of CYP2B6 substrates was found in healthy volunteers and patients. In a panel of 87 human liver microsome samples, the CYP2B6*6 allele was associated with significantly decreased protein expression and activity, measured by bupropion 4-hydroxylation and efavirenz 8-hydroxylation (17559344). The mechanism was predominantly aberrant splicing caused by c.516G>T (but not c.785A>G) leading to reduced content of functional mRNA, protein, and activity (14551287, 18171905, 24260284). Multiple in vitro studies using human liver microsomes (17559344, 22232427, (23550066) and cDNA expression systems (21659470, 32238417, 35538637) found that CYP2B6*6 has decreased enzyme activity and metabolism of efavirenz, bupropion, methadone and ketamine. Although two other in vitro studies using cDNA expression systems found increased activity (12642465, 30201214), the experts did not find these results convincing. This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Multiple studies evaluating efavirenz plasma concentrations among patients with HIV found that CYP2B6*6 carriers had higher efavirenz concentrations compared to the *1 reference (e.g., 15194512, 17235330, 27799204). A study evaluating efavirenz content in hair samples among HIV patients taking efavirenz for more than three months similarly found that CYP2B6*6 was associated with greater long term efavirenz exposure (26655325). Other studies using c.516G>T as a tagSNP for CYP2B6*6 (15622315) showed that G/T and T/T genotypes (compared to G/G) were associated with significantly higher efavirenz plasma exposure during HIV therapy. Several studies found that plasma exposure of the active bupropion metabolite hydroxybupropion was less in CYP2B6*6 carriers than in the *1 reference, although bupropion concentration and clearance were unchanged (23344581, 25565674, 29756345, 34752647). Multiple clinical studies of methadone, evaluating metabolism and/or clearance, have shown that methadone plasma exposure (S- more than R-) is greater and/or metabolism and clearance is less in CYP2B6*6 carriers compared to the *1 reference (16338275, 17178267, 17329992, 25456329, 26389554, 28723731, 32302325 ). Therefore, consensus among experts was decreased function based on strong evidence.	{"Latino": 0.21163164, "European": 0.23297834, "Oceanian": 0.62, "East Asian": 0.17446446, "Near Eastern": 0.231, "Central/South Asian": 0.185, "Sub-Saharan African": 0.37487158, "African American/Afro-Caribbean": 0.31696695}	f
777445	399	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	398	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
2899161	188	CYP2B6	*48	\N	Uncertain function	\N	\N	2899160	{38596098}	Inadequate	\N	CYP2B6*48 (c.1145T>A, p.I382N) – Uncertain function: CYP2B6*48 is assigned uncertain function due to inadequate evidence describing function. A single in vitro study reported decreased function for p.I382N using buproprion and efavirez as probes (38596098).	{"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
2899147	188	CYP2B6	*41	Decreased function	Decreased function	\N	\N	2899146	{14551287,18171905,24260284,38596098}	Limited	\N	CYP2B6*41 (c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R; c.1138T>C, p.Y380H) – Decreased function: CYP2B6*41 is assigned decreased function. CYP2B6*41 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.Y380H 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
777437	399	CYP2B6	*8	No function	No function	\N	\N	777436	{14551287,15190123,20517174,21659470,21746968,30201214}	Limited	\N	CYP2B6*8 (c.415A>G, p.K139E) - No function: CYP2B6*8 is assigned no function. Multiple in vitro studies using human liver microsomes (14551287) and cDNA expression systems (15190123, 20517174, 21659470, 21746968, 30201214) found that CYP2B6*8 had no enzyme activity compared to the *1 reference with various substrates. Therefore, consensus among experts was no 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": 0.0}	f
777447	399	CYP2B6	*13	No function	No function	\N	\N	777446	{15190123,17559344,20517174,30201214}	Limited	\N	CYP2B6*13 (c.415A>G, p.K139E; c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R) - No function: CYP2B6*13 is assigned no function. CYP2B6*13 contains the same variants as CYP2B6*6, which is assigned decreased function, and CYP2B6*8 which is assigned no function. Most in vitro studies including those using cDNA expression systems (15190123, 20517174, 30201214) and human liver microsomes (17559344) found that CYP2B6*13 has no enzyme activity; only one in vitro study using a cDNA expression system showed residual activity for artemether metabolism compared to the *1 reference. This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was no 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
777449	399	CYP2B6	*14	Decreased function	Uncertain function	\N	\N	777448	{15190123,17559344,20517174,21746968,30201214}	Limited	\N	CYP2B6*14 (c.419G>A, p.R140Q) - Uncertain function: CYP2B6*14 is assigned uncertain function. In vitro studies using human liver microsomes (17559344, 15190123) and cDNA expression systems (15190123, 20517174, 30201214, 21746968) found that CYP2B6*14 has decreased enzyme activity compared to the *1 reference. However, due to the lack of any in vivo or clinical evidence, consensus among experts was uncertain clinical function based on limited evidence.	{"Latino": 0.0016818077, "European": 0.0050876285, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.002744161, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
777597	399	CYP2C19	*36	\N	No function	\N	\N	777596	{31260137}	Limited	\N	CYP2C19*36 is assigned no function based on limited evidence. CYP2C19*36 is a complete deletion of the CYP2C19 gene and was identified by interrogation of multiple databases of clinical chromosomal microarray data (31260137). Therefore, because a gene deletion would not result in protein formation, 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": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777601	382	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
777451	399	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
777459	399	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
777463	399	CYP2B6	*22	Normal or increased function	Uncertain function	\N	\N	777462	{15722458,17235330,17559344,20624854,35194103}	Inadequate	\N	CYP2B6*22 (c.-82T>C) – Uncertain function: CYP2B6*22 is assigned uncertain function. One study in human liver microsomes found that CYP2B6*22 had increased enzyme activity towards efavirenz and bupropion compared to the *1 reference (17559344). A second study found increased levels of CYP2B6*22 mRNA expression levels in human liver tissue and enzyme activity in liver microsomes compared to the *1 reference (15722458). A recent study using human liver tissues did not find increased mRNA content or activity (35194103); this study was limited by having only two samples genotyped as CYP2B6*1*22. Therefore, the consensus among experts was uncertain function based on inadequate evidence.	{"Latino": null, "European": 0.014, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.031, "African American/Afro-Caribbean": 0.011}	f
777473	399	CYP2B6	*27	\N	Uncertain function	\N	\N	777472	{17235330,21746968,30201214}	Inadequate	\N	CYP2B6*27 (c.593T>C, p.M198T) – Uncertain function: CYP2B6*27 is assigned uncertain function. Three in vitro studies using cDNA expression systems found that CYP2B6*27 demonstrated decreased enzyme activity compared to the *1 reference for most substrates, although increased activity was seen for one non-drug probe substrate (21746968, 17235330, 30201214). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. One subject with the CYP2B6*6/*27 genotype had an elevated efavirenz AUC compared to the *1 reference (17235330). Consensus was not achieved among experts due to insufficient evidence of this variant in human subjects. Therefore, uncertain function was assigned based on inadequate evidence.	{"Latino": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.008, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.006, "African American/Afro-Caribbean": null}	f
777475	399	CYP2B6	*28	No function	No function	\N	\N	777474	{17235330,20517174,30201214}	Limited	\N	CYP2B6*28 (c.917C>G, p.T306S; c.1132C>T, p.R378X) – No function: CYP2B6*28 is assigned no function. CYP2B6*28 is defined by a nonsense mutation which results in a premature stop codon resulting in a truncated protein. One study evaluating efavirenz plasma concentrations in patients with HIV found a subject with CYP2B6 *6/*28 genotype had elevated efavirenz AUC compared to the *1 reference and CYP2B6 *6/*6 subjects (17235330). In vitro studies using cDNA expression systems found that CYP2B6*28 demonstrated no enzyme activity (17235330, 20517174). Therefore, consensus among experts was no function based on limited evidence.	{"Latino": 0.0, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.006, "African American/Afro-Caribbean": null}	f
777491	399	CYP2B6	*36	Decreased function	Decreased function	\N	\N	777490	{23418033,18171905,24260284}	Limited	\N	CYP2B6*36 (c.-82T>C, c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R) – Decreased function: CYB2B6*36 is assigned decreased function. CYP2B6*36 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information) (23418033). 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
2091253	299	CYP2D6	*160	\N	Unknown function	\N	n/a	2091252	{}	No Evidence	\N	CYP2D6*160 is assigned unknown function due to no literature describing function of this allele. CYP2D6*160 is defined by the two SNPs defining the normal function *2 allele and two additional SNPs that are also found on *82 which is cassified as unknown function.	{"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
777481	399	CYP2B6	*31	Normal function	Normal function	\N	\N	777480	{26655325,30201214}	Limited	\N	CYP2B6*31 (c.937C>A, p.L313I) – Normal function: CYP2B6*31 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*31 did not impact long term efavirenz content (26655325). An in vitro study using a cDNA expression system similarly found CYP2B6*31 demonstrated similar enzyme activity compared to the *1 reference (30201214). Therefore, consensus among experts was normal function based on limited evidence.	{"Latino": 0.0, "European": 0.000007472868, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777487	399	CYP2B6	*34	Decreased function	Decreased function	\N	\N	777486	{23418033,30201214,18171905,24260284}	Limited	\N	CYP2B6*34 (c.-82T>C, c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R; c.1459C>A, p.R487S) – Decreased function: CYP2B6*34 is assigned decreased function. CYP2B6*34 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information) (23418033). Although one in vitro study using a cDNA expression system found that CYP2B6*34 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*34. 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
777489	399	CYP2B6	*35	\N	Uncertain function	\N	\N	777488	{23418033,30201214}	Inadequate	\N	CYP2B6*35 (c.-82T>C; c.329G>T, p.G110V; c.341T>C, p.I114T; c.444G>T, p.E148D; c.593T>C, p.M198T; c.835G>C, p.A279P) – Uncertain function: CYB2B6*35 is assigned uncertain function. Two in vitro studies using cDNA expression systems provided inconclusive evidence for CYP2B6*35 function (23418033, 30201214). Therefore, consensus among experts was uncertain function based on inadequate 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
777495	399	CYP2B6	*38	No function	No function	\N	\N	777494	{23640958}	Limited	\N	CYP2B6*38 (c.186T>A, p.Y62X; c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R) – No function: CYB2B6*38 is assigned no function. CYP2B6*38 contains the variants which define CYP2B6*6 in addition to a third variant which causes a premature stop codon. CYP2B6*38 was identified in a patient taking efavirenz who developed neurologic symptoms and was found to have an efavirenz plasma concentration 40-fold above normal limit. Efavirenz was discontinued and efavirenz plasma concentrations returned to normal after 10 weeks in addition to resolution of neurologic symptoms (23640958). Therefore, consensus among experts was no 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
2899143	188	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
2899149	188	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
777431	399	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
777435	399	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
777443	399	CYP2B6	*11	Decreased function	Uncertain function	\N	\N	777442	{15190123,19916993,20517174,21746968,23734829,23778320,25303294,26779253,27045425,30201214,28886044}	Limited	\N	CYP2B6*11 (c.136A>G, p.M46V) – Uncertain function: CYP2B6*11 is assigned uncertain function. In vitro studies using cDNA expression systems demonstrated decreased or no enzyme activity compared to the *1 reference (20517174, 21746968, 15190123, 30201214). Some studies with heterozygous and homozygous CYP2B6*11 patients showed that this allele is associated with increased exposure of efavirenz (27045425, 26779253, 28886044), while other clinical studies (25303294, 23734829, 19916993, 23778320) did not consistently demonstrate decreased enzyme activity or altered PK with efavirenz. Therefore, consensus among experts was uncertain function based on consistent in vitro data but limited and inconsistent clinical evidence.	{"Latino": 0.0016810922, "European": 0.0030138378, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0021935336, "Sub-Saharan African": 0.070927635, "African American/Afro-Caribbean": 0.0024664723}	f
777457	399	CYP2B6	*19	Decreased function	Decreased function	\N	\N	777456	{16272958,21746968,30085944,30201214,31324697,32238417,35538637,18171905,24260284}	Limited	\N	CYP2B6*19 (c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R; c.1006C>T, p.R336C) – Decreased function: CYP2B6*19 is assigned decreased function. CYP2B6*19 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information). CYP2B6*19 has a unique SNP, c.1006C>T, which discriminates it from other alleles with c.516G>T. Several in vitro studies using cDNA expression systems found decreased enzyme activity for CYP2B6*19 compared to the *1 reference with various substrates (16272958, 21746968, 30201214, 30085944, 31324697, 32238417, 35538637). 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
777479	399	CYP2B6	*30	No function	No function	\N	\N	777478	{23164804,28181240}	Limited	\N	CYP2B6*30 (CYP2B7-CYP2B6 hybrid gene) – No function: CYP2B6*30 is assigned no function. This allele has a hybrid gene consisting of CYP2B6 (exons 1-4) and CYP2B7 (exons 5-9) harboring 15 amino acid changes compared to the protein encoded by the CYP2B6*1 reference. Among those is a premature stop codon (p.R378X) which is also found in CYP2B6*28 (23164804). This allele has been found in a duplication structure; it remains uncertain, however, whether the other gene in the duplication is a *1, *4 or *6 (or potentially other). Although CYP2B6*30 has no function, the function of this duplication allele depends on the nature of the other gene copy. One in vitro study found that primary human hepatocytes of subjects with a CYP2B6*30 had significantly lower mRNA and 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 *1/*30 compared to *1/*1 (28181240). In this study, the presence of a CYP2B6*30 was inferred by subjects having three gene copies and sequence analysis of the *30; however, the study did not provide any information regarding the nature of the second gene copy of the duplication. Therefore, consensus among experts was no 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
777493	399	CYP2B6	*37	Decreased or no function	Decreased function	\N	\N	777492	{23418033,30201214,18171905,24260284}	Limited	\N	CYP2B6*37 (c.516G>T, p.Q172H/splice defect; c.548T>G, p.V183G; c.785A>G, p.K262R) – Decreased function: CYB2B6*37 is assigned decreased function. CYP2B6*37 contains c.516G>T which causes aberrant splicing (see CYP2B6*6 for more information) (23418033). Multiple in vitro studies using cDNA expression systems found that CYP2B6*37 has no enzyme activity with bupropion and efavirenz compared to the *1 reference (23418033, 30201214). However, there was no in vivo data or data for liver microsomes. 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	188	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
2899153	188	CYP2B6	*44	\N	Uncertain function	\N	\N	2899152	{38596098}	Inadequate	\N	CYP2B6*44 (c.304G>A, p.A102T) – Uncertain function: CYP2B6*44 is assigned uncertain function due to inadequate evidence describing function. A single in vitro study reported decreased function for p.A102T using buproprion and efavirez as probes (38596098).	{"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
778097	395	CYP2D6	*89	\N	Uncertain function	\N	n/a	778096	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*89 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*89 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
777553	399	CYP2C19	*11	\N	Normal function	\N	\N	777552	{12464799,21325430,25001882,21692664}	Limited	\N	CYP2C19*11 is assigned normal function based on limited evidence. Three in vitro studies using different cell systems found CYP2C19*11 demonstrated similar enzyme activity compared to wildtype with mephenytoin, omeprazole, clopidogrel and other substrates (12464799, 21325430, 25001882, 21692664). 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": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777567	399	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
777585	399	CYP2C19	*30	\N	Uncertain function	\N	\N	777584	{26153442,30464555,29098786}	Inadequate	\N	CYP2C19*30 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C19*30 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. 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
777533	399	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
777551	399	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
777549	399	CYP2C19	*9	\N	Decreased function	\N	\N	777548	{12464799,21325430,25001882,21692664}	Limited	\N	CYP2C19*9 is assigned decreased function based on limited evidence. Three in vitro studies using different cell systems found CYP2C19*9 demonstrated decreased enzyme activity compared to wildtype with mephenytoin, omeprazole, and clopidogrel substrates (12464799, 21325430, 25001882). Another study found CYP2C19*9 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": 0.0008389262, "American": null, "European": 0.0006602626, "Oceanian": null, "East Asian": 0.00011504832, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.026961539, "African American/Afro-Caribbean": 0.014347053}	f
777555	399	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
777573	399	CYP2C19	*23	\N	Uncertain function	\N	\N	777572	{25001882,27578295,30464555,31713493}	Inadequate	\N	CYP2C19*23 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C19*23 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (25001882, 27578295, 30464555, 31713493). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00056672905, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777577	399	CYP2C19	*25	\N	Decreased function	\N	\N	777576	{25001882,19636337,31713493}	Limited	\N	CYP2C19*25 is assigned decreased function based on limited in vitro and computational evidence. An in vitro study found CYP2C19*25 had decreased intrinsic clearance compared to wildtype with clopidogrel and mephenytoin, and omeprazole substrates (25001882, 31713493). A computational analysis of the Phe448Leu amino acid substitution in CYP2C19*25 predicted the change as deleterious. An examination of the structure showed the amino acid substitution, which is important for the heme-binding region, could disrupt the hydrophobic pocket in the region (19636337). 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": 0.00018712576, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777583	399	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
777587	399	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
777535	399	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
777565	399	CYP2C19	*17	\N	Increased function	\N	\N	777564	{16413245,17625515,20083681,17625515,32857933,29325448,29136336,31649299,20083681}	Definitive	\N	CYP2C19*17 is assigned increased function based on strong evidence in homozygous and heterozygous subjects. Subjects with CYP2C19 *1/*17 and CYP2C19 *17/*17 genotype demonstrated increased omeprazole metabolism compared to wildtype subjects based on plasma metabolite measurements. The predicted AUC of omeprazole in CYP2C19*17/*17 patients was 63% of the predicted AUC in wildtype subjects. Additionally, in a separate population, CYP2C19*17/*17 subjects demonstrated increased mephenytoin metabolism compared to wildtype and CYP2C19 *1/*17 subjects. A murine study found increased gene transcription of CYP2C19*17 likely results in the observed increased enzyme activity (16413245). CYP2C19 *17/*17 patients taking escitalopram had 42% serum escitalopram concentrations compared to wildtype (17625515). Also, in adolescents with generalized anxiety disorder, patients with *4/*17 or *17/*17 had lower AUC/CMAX compared to normal (*1/*1) and poor metabolizers and expected differences in the ratios of s-citalopram to its metabolite, desmethylcitalopram (PMID 32857933). Additionally, CYP2C19 *1/*17 and *17/*17 carriers in naturalistically studied depressed adults had 10% and 20% lower serum concentration compared to CYP2C19 NMs (29325448). In healthy adults, *17/*17 was associated with lower sertraline AUC vs normal metabolizers (29136336), although in a separate study involving more than 1200 patients, the CYP2C19*17 allele was associated with 8% lower serum concentration compared to NMs (31649299). CYP2C19 *17/*17 patients taking clopidogrel had lower ADP induced platelet aggregation likely as a result of increased clopidogrel metabolism to its active metabolite compared to wildtype and CYP2C19 *1/*17 patients (20083681). Therefore, consensus among experts was increased function based on strong evidence.	{"Latino": 0.16655846, "American": 0.086080186, "European": 0.2154386, "Oceanian": 0.057, "East Asian": 0.020541333, "Near Eastern": 0.1914227, "Central/South Asian": 0.17077276, "Sub-Saharan African": 0.17333587, "African American/Afro-Caribbean": 0.2072274}	f
777745	399	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
1406320	381	CYP2C9	*74	Unknown function	Unknown function	\N	n/a	1406319	{}	No evidence	\N	CYP2C9*74 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
777737	399	CYP2C9	*35	No function	No function	\N	0.0	777736	{23752738,24322786,2145143}	Limited	\N	CYP2C9*35 is assigned no function based on limited evidence in one heterozygous subject and in vitro studies. CYP2C9*35 was first described in a patient requiring a very low weekly warfarin dose of 2.25mg (2145143). No variant was observed in VKORC1 or CYP4F2 in this patient and a subsequent in silico study showed a decreased interaction with reductase resulting in impaired enzyme activity. In vitro studies similarly found CYP2C9*35 demonstrated no enzyme activity with warfarin, tolbutamide, and diclofenac substrates (23752738, 24322786). 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": null}	f
777753	399	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
777703	399	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
777755	399	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
777761	399	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
777767	399	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	399	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
777781	399	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
777807	381	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	381	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
777679	399	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
777715	399	CYP2C9	*24	No function	No function	\N	0.0	777714	{23752738,17332144,16543980}	Limited	\N	CYP2C9*24 is assigned decreased function based on limited evidence in a heterozygous patient and in vitro studies. A patient on a stable dose of warfarin with CYP2C9 *2/*24 genotype had the lowest daily warfarin dose requirement and warfarin clearance based on plasma concentrations compared to patients with CYP2C9 *1/*2 genotype and matched for age, warfarin indication and co-administrated medications (16543980). An in vitro study similarly found CYP2C9*24 exhibited no enzyme activity with warfarin or tolbutamide substrates (23752738). No CYP2C9*24 protein was detected in a separate in vitro study suggesting the enzyme may be improperly folded (17332144). 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": 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
777965	395	CYP2D6	*15	\N	No function	\N	0.0	777964	{8807669}	Limited	\N	CYP2D6*15 is assigned no function based on limited evidence. CYP2D6*15 was first described in a subject demonstrating markedly decreased dextromethorphan and debrisoquine metabolism (8807669). CYP2D6*15 is defined by an amino acid insertion resulting in missense sequence and premature stop codon, 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": 0.0, "American": 0.0009130435, "European": 0.0004858789, "Oceanian": 0.0, "East Asian": 0.00009106044, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0023071566, "African American/Afro-Caribbean": 0.0}	f
778029	395	CYP2D6	*48	\N	Normal function	\N	1.0	778028	{18784265,24647041,30366777}	Limited	\N	CYP2D6*48 is assigned normal function based on limited evidence. Multiple in vitro studies found CYP2D6*48 had similar enzyme activity compared to wildtype with multiple substrates (18784265, 24647041, 30366777). Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00024301164, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777695	399	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
777697	399	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
777705	399	CYP2C9	*19	Uncertain function	Uncertain function	\N	n/a	777704	{23752738,23844998,24118918,25142737,25476996,25144335,25951663,25614704,25832633,25884291,27163851,24077631,16099926}	Inadequate evidence	\N	CYP2C9*19 is assigned uncertain function due to inadequate evidence. One subject with CYP2C9*1/*19 genotype exhibited decreased clearance compared to wildtype subjects based on tolbutamide plasma concentrations and urine metabolite concentrations after one 500mg dose. This result correlated with the in vitro study where CYP2C9*19 demonstrated 31% enzyme activity with a tolbutamide substrate compared to wildtype (25614704). Multiple in vitro studies similarly found CYP2C9*19 demonstrated decreased clearance with various substrates compared to wildtype (23752738, 23844998, 24118918, 25142737, 25476996, 25144335, 25951663, 25832633, 25884291, 27163851, 24077631), however, one in vitro study showed CYP2C9*19 had similar activity compared to wildtype with a tolbutamide substrate (16099926). Consensus was not achieved among experts and therefore uncertain function was assigned but experts agreed additional evidence may change the assignment to decreased function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.00047686882, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777717	399	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
778129	394	CYP2D6	*105	\N	Unknown function	\N	n/a	778128	{}	No Evidence	\N	CYP2D6*105 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": 0.006, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777743	399	CYP2C9	*38	Decreased function	Decreased function	\N	0.5	777742	{24077631,24118918,25142737,25144335,25951663,25476996,25832633,25884291,25924705,27163851,28758225,23844998}	Limited	\N	CYP2C9*38 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*38 demonstrated decreased clearance compared to wildtype for multiple substrates (24077631, 24118918, 25144335, 25951663, 25476996, 25832633, 25884291, 25924705, 23844998). Although two in vitro studies showed CYP2C9*38 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 activity and similar activity compared to wildtype in these studies (25142737, 27163851). Additionally, the experts did not deem an in vitro study where CYP2C9*38 demonstrated activity ranging from decreased to increased compared to wildtype with 7-ethoxycoumarin, flavanone, and steroid substrates (28758225) as convincing evidence because it could not be ruled out that these results which differed from the majority of in vitro studies were due to the specific system used in the study. 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
777747	399	CYP2C9	*40	Uncertain function	Uncertain function	\N	n/a	777746	{24077631,24118918,25142737,25951663,25144335,25476996,25614704,25832633,25884291,25924705,27163851,28758225,23844998}	Inadequate evidence	\N	CYP2C9*40 is assigned uncertain function due to inadequate evidence in one heterozygous subject and in vitro studies. One subject with CYP2C9 *1/*40 genotype exhibited decreased AUC and half-life but similar oral clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704). In vitro studies found CYP2C9*40 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (24077631, 24118918, 23844998, 25142737, 25144335, 25951663, 25476996, 25832633, 25884291, 25924705, 27163851, 28758225, 25614704). 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
777749	399	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
777683	399	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
1406316	381	CYP2C9	*72	Unknown function	Unknown function	\N	n/a	1406315	{}	No evidence	\N	CYP2C9*72 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
778151	394	CYP2D6	*116	\N	Unknown function	\N	n/a	778150	{}	No Evidence	\N	CYP2D6*116 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
2091251	299	CYP2D6	*159	\N	Unknown function	\N	n/a	2091250	{}	No Evidence	\N	CYP2D6*159 is assigned unknown function due to no literature describing function of this allele. CYP2D6*159 is defined by the two SNPs defining the normal function *2 allele and one additional 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
777725	399	CYP2C9	*29	Decreased function	Decreased function	\N	0.5	777724	{23752738,16788382,23844998,24118918,25142737,25951663,25144335,25476996,25614704,25832633,25884291,25924705,27163851,24077631}	Limited	\N	CYP2C9*29 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*29 demonstrated decreased clearance compared to wildtype (23752738, 23844998, 24118918, 25951663, 25144335, 25476996, 25832633, 25884291, 25924705, 24077631). Although two in vitro studies showed CYP2C9*29 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). Other studies, however, also showed CYP2C9*29 has similar clearance compared to wildtype (16788382, 25614704). Although the experts recognized there is conflicting evidence, the experts did not find it convincing as it was determined the activity of CYP2C9*29 toward most substrates was similar to CYP2C9*2 which definitively has decreased function. Therefore, consensus among experts was decreased function with an activity value of 0.5.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0022081658, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777741	399	CYP2C9	*37	Decreased function	Decreased function	\N	0.5	777740	{24077631,24118918,25142737,25144335,25951663,25476996,25832633,25884291,25924705,27163851,23844998}	Limited	\N	CYP2C9*37 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*37 demonstrated decreased clearance compared to wildtype with multiple substrates (24077631, 24118918, 25951663, 25476996, 25832633, 25924705, 27163851, 23844998). Although two in vitro studies showed CYP2C9*37 had similar activity compared to wildtype, the experts did not find these results convincing as in these studies CYP2C9*3 which definitively has no function, demonstrated increased activity compared to wildtype in these studies (25142737, 25884291). An additional in vitro study showed CYP2C9*37 had similar activity compared to wildtype (25144335), however, the experts did not find this result convincing as the function of CYP2C9*37 demonstrated decreased function toward the majority of substrates. 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": 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
777763	399	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
778177	395	CYP2D6	*129	\N	No function	\N	0.0	778176	{32759992}	Limited	\N	CYP2D6*129 is assigned no function based on limited evidence. CYP2D6*129 is defined by an premature stop codon predicted to yield truncated protein and thus be nonfunctional. 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 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
778027	395	CYP2D6	*47	\N	No function	\N	0.0	778026	{18784265,24647041,30366777}	Limited	\N	CYP2D6*47 is assigned no function based on limited evidence. Multiple in vitro studies found CYP2D6*47 had nondetectable enzyme activity with multiple substrates (18784265, 24647041, 30366777). 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": 0.0003937946, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778059	395	CYP2D6	*63	\N	Uncertain function	\N	n/a	778058	{24647041,30366777}	Inadequate	\N	CYP2D6*63 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*63 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": 0.00028595122, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778111	395	CYP2D6	*96	\N	No function	\N	0.0	778110	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Limited	\N	CYP2D6*96 is assigned no function based on limited evidence. Multiple in vitro studies found CYP2D6*96 had nondetectable enzyme with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). CYP2D6*96 is defined by an early stop codon yielding a truncated 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
778117	395	CYP2D6	*99	\N	No function	\N	0.0	778116	{29327975}	Limited	\N	CYP2D6*99 is assigned no function based on limited evidence. CYP2D6*99 has been described in a subject with CYP2D6*5/*99 genotype demonstrating markedly decreased metabolism compared to wildtype with dextromethorphan and venlafaxine substrates (29327975). CYP2D6*99 is defined by the same SNPs as CYP2D6*10 in addition to a SNP resulting in an amino acid substitution which disrupts enzyme activity yielding a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.002, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778125	394	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
778135	394	CYP2D6	*108	\N	Unknown function	\N	n/a	778134	{}	No Evidence	\N	CYP2D6*108 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": 0.003, "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
778137	394	CYP2D6	*109	\N	Decreased function	\N	0.25	778136	{11470994,1844820,8101460,11266079,24647041,30366777}	Limited	\N	CYP2D6*109 is assigned decreased function based on limited evidence. *109 has the 2616delAAG (also present in *9 with decreased function-PMID 1844820; 8101460; 11266079; 24647041; 30366777) and 3184G>A (V338M) which is a core SNP of *29. One study compared activity of V338M vs that of V136I (both present in *29) and found that both decrease activity in vitro (PMID 11470994). Because both variants have been shown to have decreased function in vitro, consensus of the experts was decreased function with 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
778173	394	CYP2D6	*127	\N	Unknown function	\N	n/a	778172	{}	No Evidence	\N	CYP2D6*127 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
2091241	299	CYP2D6	*154	\N	Uncertain function	\N	n/a	2091240	{}	Inadequate	\N	CYP2D6*154 is assigned uncertain function due to inadequate evidence. CYP2D6*154 is defined by the three SNPs defining the decreased function *17 allele and one additional SNP that defines *75 which is classified as uncertain function.	{"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
2091247	299	CYP2D6	*157	\N	Unknown function	\N	n/a	2091246	{}	No Evidence	\N	CYP2D6*157 is assigned unknown function due to no literature describing function of this allele. CYP2D6*157 is defined by the five SNPs defining the decreased function *29 allele and one additional 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
2091255	299	CYP2D6	*161	\N	No function	\N	0.0	2091254	{}	limited	\N	CYP2D6*161 is assigned no function based on limited evidence. CYP2D6*161 is defined by the two SNPs defining the normal function *2 allele and two SNP that are only found on this star allele of which one, 2591_2592insT causes a premature stop codon (E273X) that likely renders the allele nonfunctional.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.00208, "African American/Afro-Caribbean": null}	f
5294111	92	CYP2D6	*28x2	\N	Uncertain function	\N	n/a	777988	{24647041,30366777}	Inadequate	\N	CYP2D6*28x2 was deposit into PharmVar. CYP2D6*28 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*28 demonstrated enzyme activity ranging from nondetectable to similar activity compared to wildtype with various substrates (24647041, 30366777). Therefore, consensus among experts was uncertain function for CYP2D6*28. CYP2D6*28x2 is also assigned uncertain function as it cannot yet be determined what the phenotype of a duplicated allele with uncertain function would be clinically similar to.	{"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
779744	326	CYP2D6	*43x2	\N	Uncertain function	\N	n/a	778018	{24647041,30366777}	Inadequate	\N	CYP2D6*43x2 is assigned uncertain function due to inadequate evidence. CYP2D6*43 is assigned uncertain function due to inconsistent findings regarding enzyme activity compared to wildtype (24647041, 30366777). Therefore, consensus among experts was uncertain function as it cannot yet be determined what the phenotype of a duplicated allele with uncertain function would be clinically similar to.	{"Latino": null, "American": 0.001, "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": 0.0}	f
778021	395	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
779747	326	CYP2D6	*45x2	\N	Increased function	\N	2.0	778022	{15768052,24647041}	Limited	\N	CYP2D6*45x2 is assigned increased function based on limited evidence. CYP2D6*45 is assigned normal function (15768052; 24647041). Therefore, consensus among experts was increased function with an activity value of 2 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 distinct from phenotypes comprising normal function alleles.	{"Latino": 0.0, "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": 0.0010954796}	f
778113	395	CYP2D6	*97	\N	Uncertain function	\N	n/a	778112	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*97 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*97 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
778119	395	CYP2D6	*100	\N	No function	\N	0.0	778118	{23394389}	Limited	\N	CYP2D6*100 is assigned no function based on limited evidence. CYP2D6*100 has been described in a subject with CYP2D6*5/*100 genotype demonstrating markedly decreased dextromethorphan metabolism compared to wildtype (23394389). CYP2D6*100 is defined by the same SNPs as CYP2D6*10 in addition to a 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
778157	394	CYP2D6	*119	\N	Decreased function	\N	0.25	778156	{11037799,15289790,17001295,17112815,19364831}	Limited	\N	CYP2D6*119 is assigned decreased function wiht an activity value of 0.25 due to limited evidence describing function of this allele. *119 contains the splice SNP 2989G>A that is also found in *41 (decreased function; 11037799; 15289790; 17001295; 17112815; 19364831). Therefore, consensus among experts was decreased function due to limited evidence.	{"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": 0.0, "African American/Afro-Caribbean": 0.0}	f
778175	394	CYP2D6	*128	\N	Uncertain function	\N	n/a	778174	{32759992}	Inadequate	\N	CYP2D6*128 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 3.3% compared to *1 for tamoxifen N-desmethylation (32759992); no activity was detectable for dextromethorphan O-demethylation. 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
778478	380	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	380	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
777959	395	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
777995	395	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
778025	395	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
778037	395	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
778109	395	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
778127	394	CYP2D6	*104	\N	Unknown function	\N	n/a	778126	{}	No Evidence	\N	CYP2D6*104 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
778147	395	CYP2D6	*114	\N	No function	\N	0.0	778146	{10064570,18784265,24647041}	Limited	\N	CYP2D6*114 is assigned no function based on limited evidence. CYP2D6*114 has been described in a subject with CYP2D6*5/*114 genotype demonstrating poor debrisoquine metabolism (10064570). Multiple in vitro studies found CYP2D6*114 had nondetectable enzyme activity with various substrates (18784265, 24647041). 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": 0.0007862866, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778155	394	CYP2D6	*118	\N	Unknown function	\N	n/a	778154	{}	No Evidence	\N	CYP2D6*118 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
777969	395	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
777975	395	CYP2D6	*21	\N	No function	\N	0.0	777974	{10471060,15618746}	Limited	\N	CYP2D6*21 is assigned no function based on limited evidence. CYP2D6*21 has been described in subjects demonstrating markedly decreased metabolism of debrisoquine and dextromethorphan (10471060, 15618746). CYP2D6*21 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": null, "East Asian": 0.0035356972, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778007	395	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	395	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
778161	394	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
778165	394	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
778167	395	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
778179	394	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
778344	386	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
778462	380	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
1777311	300	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
1609528	301	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
777947	395	CYP2D6	*6	\N	No function	\N	0.0	777946	{10022755,7894499,7951238,7868129}	Strong	\N	CYP2D6*6 is assigned no function based on strong evidence. CYP2D6*6 has been described in subjects demonstrating decreased metabolism of various CYP2D6 substrates (10022755, 7894499, 7951238, 7868129). 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 strong evidence.	{"Latino": 0.0051102643, "American": 0.0025018877, "European": 0.011197059, "Oceanian": 0.0, "East Asian": 0.00015815398, "Near Eastern": 0.00543274, "Central/South Asian": 0.00040183793, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0028887512}	f
778013	395	CYP2D6	*40	\N	No function	\N	0.0	778012	{12152006,12811367,24647041,30366777}	Moderate	\N	CYP2D6*40 is assigned no function based on moderate evidence in heterozygous subjects and in vitro studies. CYP2D6*40 is defined by an 18 base pair insertion. CYP2D6*40 has been described in subjects with CYP2D6 *4/*40, CYP2D6 *6/*40, and CYP2D6 *40/*42 genotype demonstrating poor metabolism with a dextromethorphan substrate (12152006, 12811367). Multiple in vitro studies found CYP2D6*40 had nondetectable enzyme activity compared to wildtype with various substrates (24647041, 30366777). Therefore, consensus among experts was no function with an activity value of 0 based on moderate evidence.	{"Latino": null, "American": 0.0, "European": 0.00069944287, "Oceanian": 0.0, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.013845487, "African American/Afro-Caribbean": 0.004642406}	f
778023	395	CYP2D6	*45	\N	Normal function	\N	1.0	778022	{15768052,24647041,30366777}	Limited	\N	CYP2D6*45 is assigned normal function based on limited evidence. Subjects with CYP2D6 *5/*45 genotype demonstrated similar dextromethorphan metabolism compared to wildtype subjects (15768052). In vitro studies found CYP2D6*45 demonstrated similar activity compared to wildtype with dextromethorphan and bufuralol substrates (15768052, 24647041). Although one in vitro study found CYP2D6*45 demonstrated decreased clearance compared to wildtype with a primaquine substrate (30366777) the experts did not find this result convincing as CYP2D6*45 demonstrated similar activity compared to wildtype towards a majority of substrates as well as in vivo. Therefore, consensus among experts was normal function with an activity value of 1 based on limited evidence.	{"Latino": null, "American": 0.003, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.038135953, "African American/Afro-Caribbean": 0.05011446}	f
778181	394	CYP2D6	*131	\N	Uncertain function	\N	n/a	778180	{32759992}	Inadequate	\N	CYP2D6*131 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 3.8% and 2.3% compared to *1 for tamoxifen N-desmethylation and dextromethorphan O-demethylation, respectively. 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
777985	395	CYP2D6	*26	\N	Uncertain function	\N	n/a	777984	{18838503,24647041,30366777}	Inadequate	\N	CYP2D6*26 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*26 demonstrated enzyme activity ranging from increased to decreased activity compared to wildtype with various substrates (18838503, 24647041, 30366777). Therefore, consensus among experts was uncertain function.	{"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": null, "African American/Afro-Caribbean": 0.0}	f
778011	395	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
778456	380	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
778460	380	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
778466	380	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
778472	380	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	380	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
778087	395	CYP2D6	*84	\N	Uncertain function	\N	n/a	778086	{28290770}	Inadequate	\N	CYP2D6*84 is assigned uncertain function due to inadequate evidence. A subject with CYP2D6 *12/*84 demonstrated decreased dextromethorphan metabolism based on urine metabolites (28290770). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"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
778093	395	CYP2D6	*87	\N	Uncertain function	\N	n/a	778092	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*87 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*87 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
778143	394	CYP2D6	*112	\N	Uncertain function	\N	n/a	778142	{31368850}	Inadequate	\N	CYP2D6*112 is assigned uncertain function. CYP2D6*112 is defined by a SNP which in silico studies predict to be a benign 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": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.002, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
8104057	2	CYP2D6	*13+*1	\N	Normal function	\N	1.0	8104056	{}	\N	\N	\N	{"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
8104058	2	CYP2D6	*13+*1x2	\N	Increased function	\N	2.0	8104056	{}	\N	\N	\N	{"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
8104062	2	CYP2D6	*13+*68x2+*4	\N	No function	\N	0.0	8104061	{}	\N	\N	\N	{"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
8104064	2	CYP2D6	*36x2+*10	\N	Decreased function	\N	0.25	8104063	{}	\N	\N	\N	{"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
8104053	2	CYP2D6	*68+*4	\N	No function	\N	0.0	8104052	{}	\N	\N	\N	{"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
3827919	172	MT-RNR1	m.1556C>T	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827918	{15141753}	Inadequate evidence	\N	MT-RNR1 1556C>T is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. Case report of of a patient with streptomycin-induced tinnitus carrying this variant (15141753) . Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.000031612555, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null}	f
6481219	39	NAT2	*31	Slow	Decreased function	\N	\N	6481218	{19909761,15564878}	Moderate	\N	NAT2*31 is assigned decreased function based on moderate evidence. NAT2*31 is characterized by the core SNVs c.70T>A (p.L24I) and c.341T>C (p.I114T). Published in silico modeling predicts that c.70T>A (p.L24I) does not impair NAT2 protein function (19909761). However, five out of ten variant effect predictors tested by CPIC staff predict that c.70T>A (p.L24I) impairs protein function and structure-based predictors suggest that c.70T>A (p.L24I) decreases protein stability which could lead to decreased function. c.341T>C (p.I114T, defining NAT2*5) has repeatedly shown decreased NAT2 N-acetylation activity in numerous in vivo and in vitro studies and five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. Additionally, an 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*31 would presumably be degraded in the same manner and is assigned decreased function based on the function of c.341T>C (p.I114T). Despite this, it remains unknown whether c.70T>A has any combinatorial effects with c.341T>C.	\N	f
3827873	172	MT-RNR1	m.663A>G	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827872	{8414970,7689389,7550368}	Inadequate evidence	\N	MT-RNR1 663A>G is assigned an uncertain risk of aminoglycoside-induced hearing loss based on inadequate evidence. This variant has been identified in individuals with aminoglycoside-induced hearing loss but also in controls after aminoglycoside exposure (8414970, 7689389, 7550368). Therefore, consensus among experts is that there is uncertain risk of aminoglycoside-induced hearing loss associated with this variant.	{"European": 0.0014543316, "East Asian": 0.04993, "Near Eastern": 0.0, "Central/South Asian": 0.003349, "Sub-Saharan African": null}	f
3827901	172	MT-RNR1	m.961T>del+Cn	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827900	{10326749,12037390,7550368,20171168}	\N	\N	MT-RNR1 961>del+Cn 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 three studies and one case report (10326749, 12037390, 7550368); however, one study found this variant in patients without aminoglycoside-induced hearing loss (20171168). Therefore, consensus among experts is that there is uncertain risk of aminoglycoside-induced hearing loss associated with this variant.	{"European": 0.002636598, "East Asian": 0.04951802, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.06856881}	f
3827911	172	MT-RNR1	m.1494C>T	Conformational change to the mitochondrial 12s rRNA leading to binding of aminoglycoside antibiotics	increased risk of aminoglycoside-induced hearing loss	\N	\N	3827910	{14681830,16380089,17085680,17434445,17698030,17698299,18830133,19682603,20100600,21205314,27397648,29876232,15722487,14681831,19687236,28103015,25474306}	Strong	\N	MT-RNR1 1494C>T is assigned an increased risk of aminoglycoside-induced hearing loss based on strong evidence. Screening of individuals or probands of individuals with aminoglycoside-hearing looss identified 1494C>T in a number of cases (14681830, 16380089, 17085680, 17434445, 17698030, 17698299, 18830133, 19682603, 20100600, 21205314, 27397648, 29876232). LCLs and/or cybrind cell lines with 1494C>T mutation have reduced growth in the presence of aminoglycosides (14681830, 15722487). Paromomycin shows increased binding to rRNA constructs carrying the T allele (19687236). Increased Kd for neomycin binding to A-site constructs carrying the T allele compared to those carrying the C allele (28103015). Cybrid lines with the 1494C>T mutation grown in gentamicin have reduced ATP production and altered mitochondria morphology (25474306). Therefore, consensus among experts was this variant is associated with increased risk of aminoglycoside-induced hearing loss based on strong evidence.	{"European": 0.00034900234, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0006698, "Sub-Saharan African": 0.0}	f
6481217	39	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
6481231	39	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
6481247	39	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
6481281	39	NAT2	*62	Slow	Decreased function	\N	\N	6481280	{}	Moderate	\N	NAT2*62 is assigned decreased function based on moderate evidence. NAT2*62 is characterized by the core SNVs c.536A>G (p.H179R), 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.536A>G (p.H179R). Ten out of ten variant effect predictors tested by CPIC staff predict that c.536A>G (p.H179R) does not impair 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*62 is assigned decreased function based on c.590G>A. Despite this, the combinatorial effects associated with c.536A>G and c.590G>A are uncertain	\N	f
7219573	23	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	23	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
6481227	39	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
6481235	39	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
6481275	39	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
6481285	39	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
779079	379	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
779425	377	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
6481253	39	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
6481283	39	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
7219575	23	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
779477	377	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
3685349	190	RYR1	c.488G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685348	{35849058}	\N	\N	PS4_Sup, PM1, PP3_Mod	{"Latino": 0.0000167, "European": 0.00000339, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.000011, "Sub-Saharan African": 0.000040}	f
6481193	39	NAT2	*4	Rapid	Increased function	\N	\N	6481192	{9154882,8781741,28653770,8102597,30564082,15558239,7668286,2376572,1451720,10744128,22092036,1872889,8689813,20040334,9333101,17011540,22970273,16531626,15565348,9321764,9110365,11214777,31257615,29018032,24702251,24444407,15110095,27509179,11773863,20801937,16003747,21750470,23899363,9565293,9891107,9682266,24221535,22105431,8287065,27223070,8001235,8923605,10762005,8081359,35928262,28752039,17505821,21946899,16570187,15032315,18167504,17434923,33815485,18680467,19336229,15564878,7669073,11337936,12222688,17264801}	Definitive	\N	NAT2*4 is assigned increased function based on definitive evidence. The NAT gene nomenclature committee considered NAT2*4 as the reference allele for over two decades before the transfer of NAT2 allele nomenclature to PharmVar, which uses the GRCh38 (NC_000008.11) reference sequence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the reference NAT2*4 allele as "rapid". Under the CPIC allele function terminology, rapid acetylation alleles are categorized as "Increased Function". NAT2*4 has been studied for more than 25 years and numerous clinical and in vitro studies have demonstrated rapid acetylation by NAT2*4 with various substrates. Early clinical studies demonstrate rapid acetylation of caffeine metabolites in individuals homo- or heterozygous for the NAT2*4 allele (8102597, 7668286, 8923605, 9891107). Additional clinical studies demonstrate rapid acetylation by NAT2*4 using isoniazid (2376572, 9321764, 15565348) and sulfamethazine (1872889, 21946899). Individuals homo- or heterozygous for NAT2*4 metabolize hydralazine rapidly (24702251, 31257615). NAT2*4 is distinguished from NAT2*1 by the presence of the core SNV c.803G>A (p.R268K). c.803G>A (p.R268K) has not been shown experimentally to alter NAT2 acetylation activity in vitro nor in vivo. Accordingly, nine out of nine variant effect predictors tested by CPIC staff predict that c.803G>A is neutral/tolerated for protein function.	\N	f
6481195	39	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
6481197	39	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
3685753	190	RYR1	c.9649T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685752	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685773	190	RYR1	c.10097G>A	Likely Benign	Normal function	\N	n/a	3685772	{33767344}	\N	\N	BS1	{"Latino": 0.001383, "European": 0.0013343602, "East Asian": 0.0000223, "Near Eastern": 0.00084150804, "Central/South Asian": 0.000549, "Sub-Saharan African": 0.0001333}	f
3685833	190	RYR1	c.12115A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685832	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685961	190	RYR1	c.14782A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685960	{35849058}	\N	\N	PM1_Sup	{"Latino": null, "European": 0.0000147, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685969	190	RYR1	c.14817C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685968	{35849058}	\N	\N	PS4_Sup, PM1_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685979	190	RYR1	c.14968A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685978	{35849058}	\N	\N	PS4_Sup, PM1_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685383	190	RYR1	c.947G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685382	{35849058}	\N	\N	PM1, PP3_Mod	{"Latino": null, "European": 0.0000008474, "East Asian": 0.0002005, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685413	190	RYR1	c.1411C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685412	{35849058}	\N	\N	PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779189	378	RYR1	c.6488G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779188	{33767344}	\N	\N	PS3_Mod, PS4, PM1, PP1_St, PP3_Mod, BS2	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
6481203	39	NAT2	*14	Slow	Decreased function	\N	\N	6481202	{8102597,9154882,28653770,7668286,22092036,9110365,24444407,21750470,9565293,24221535,10762005,8081359,17505821,21946899,17434923,18680467,11337936,29273096}	Definitive	\N	NAT2*14 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*14 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". ". NAT2*14 is characterized by the core SNVs c.191G>A (p.R64Q) 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.191G>A (p.R64Q) has been studied for more than 25 years and has shown decreased NAT2 N-acetylation activity in both clinical and in vitro studies using various substrates. Clinical studies demonstrate that individuals homozygous for NAT2*14 or heterozygous for NAT2*14 in combination with another decreased function allele exhibit decreased acetylation activity toward caffeine metabolites (8102597, 7668286, 9110365, 9565293, 21750470, 24221535, 28653770), isoniazid (9154882, 17505821), sulfamethazine (21946899), and dapsone (10762005). Six out of ten variant effect predictors tested by CPIC staff predict that c.191G>A (p.R64Q) impairs protein function. Published in silico modeling predicts that c.191G>A decreases protein stability and hinders electrostatic interactions (18680467). In vitro studies have demonstrated that NAT2*14 exhibits decreased protein expression and thermostability compared to the former reference, NAT2*4 (11337936, 17434923, 8081359).	\N	f
6481215	39	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
6481251	39	NAT2	*47	Slow	Decreased function	\N	\N	6481250	{18680467,19909761,24533708}	Limited	\N	NAT2*47 is assigned decreased function based on limited evidence. NAT2*47 is characterized by the core SNVs c.191G>A (p.R64Q), c.683C>T (p.P228L), 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.683C>T (p.P228L) impairs protein function based on the exposure of hydrophobic residues that may facilitate protein aggregation and/or targeted protein degradation (19909761). However, two out of ten variant effect predictors tested by CPIC staff predict that c.683C>T (p.P228L) impairs protein function. c.191G>A (p.R64Q, defining NAT2*14) has repeatedly shown decreased NAT2 function in numerous in vivo and in vitro studies. Six out of ten variant effect predictors tested by CPIC staff predict that c.191G>A (p.R64Q) impairs protein function. Published in silico modeling predicts that c.191G>A (p.R64Q) decreases protein stability and hinders electrostatic interactions (18680467). A NAT2 phenotyping study identified one patient with the genotype NAT2*5/*47 and this individual was classified a "slow acetylator" (24533708). In this study, slow acetylators exhibited lower metabolic ratios of acetyl-INH/INH that were statistically significant compared to both rapid and intermediate acetylators, as well as an increased INH half-life, increased INH AUC values, and decreased INH CL/F values (24533708). NAT2*47 is assigned decreased function based on the function of c.191G>A (p.R64Q). Despite this, it remains unknown whether there are any combinatorial effects associated with c.683C>T and c.191G>A	\N	f
7096549	25	NAT2	*68	Slow	Decreased function	\N	\N	7096548	{18680467}	Moderate	\N	NAT2*68 is assigned decreased function based on moderate evidence. NAT2*68 is characterized by the core SNVs c.580C>G (p.L194V), 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.580C>G (p.L194V). Six out of ten variant effect predictors tested by CPIC staff predict that c.580C>G (p.L194V) 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*68 is assigned decreased function based on c.857G>A. Despite this, the combinatorial effects associated with c.580C>G and c.857G>A are uncertain	\N	f
7096551	25	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
1002694	371	SLCO1B1	*41	\N	No function	\N	\N	1002693	{39511784,34887219,27602404,39644095,40047317,22232210,35631530}	Strong	\N	SLCO1B1*41 is assigned no function based on strong evidence. SLCO1B1*41 is defined by c.481+1G>T which disrupts a canonical splice site. An individual genotyped SLCO1B1*31/*41 exhibited an elevated plasma concentration of coproporphyrin I, at a level comparable to that in SLCO1B1*15/*15 patients (39511784). Individuals compound heterozygous for *41 experienced statin-induced rhabdomyolysis (34887219, 39511784). SLCO1B1*41 was significantly associated with altered hexadecanedioate and SLCO1B1-associated oxylipins levels in individuals with *41 vs those without (27602404, 39644095). A large clinical study demonstrated that individuals with SLCO1B1*41 exhibited significantly increased bilirubin levels relative to those without, however there was no significant association with statin-induced myotoxicity (40047317). Additionally, SLCO1B1 loss-of-function has been implicated in the pathogenesis of Rotor syndrome and SLCO1B1*41 has been identified in affected families (22232210). The variant effect predictors CADD and PhD-SNPg predict that c.481+1G>T impairs protein function, which is supported by a published in silico analysis (35631530). Expression of a truncated protein due to aberrant splicing is also supported by SpliceAI predictions.	{"American": null, "European": 0.00010, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779306	377	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
779338	378	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
779399	377	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
779459	377	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
779461	377	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
779463	377	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
779467	377	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
779471	377	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
779453	377	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
779437	377	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
779397	377	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
779411	377	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
779413	377	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
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