778111	400	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	400	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	399	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	399	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
1103378	306	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	304	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
778119	400	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	399	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
778173	399	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
778177	400	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
3685795	195	RYR1	c.11120G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685794	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777959	400	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
778113	400	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
2091241	304	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	304	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	304	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
778715	356	G6PD	202G>A_376A>G_1264C>G	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778714	{18677765,22293322}	limited	\N	Function assigned based on the WHO recommendations and in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
828096	241	MT-RNR1	Reference	\N	Normal risk of aminoglycoside-induced hearing loss	\N	\N	828095	{27654872}	\N	\N	27654872: N/A	\N	f
778093	400	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
778105	400	CYP2D6	*93	\N	Uncertain function	\N	n/a	778104	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*93 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*93 demonstrated decreased enzyme activity compared to wildtype with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). 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
778143	399	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
778147	400	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
778161	399	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	399	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	400	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	399	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
778181	399	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
779149	241	RYR1	Reference	Benign	Normal function	\N	n/a	779148	{}	\N	\N	\N	\N	f
778101	400	CYP2D6	*91	\N	Decreased function	\N	0.25	778100	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Limited	\N	CYP2D6*91 is assigned decreased function with an activity value of 0.25 due to limited evidence. *91 contains 2989G>A splicing SNP found in *41 (decreased function). In vitro studies found CYP2D6*91 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): however, in the cases of normal activity, the effect of the 2989G>A splice SNP found in *41 was not captured in the in vitro system utilized which may explain activity comparable to *1 or *2. Therefore, consensus among experts was decreased function 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
778193	399	CYP2D6	*137	\N	Uncertain function	\N	n/a	778192	{32759992}	Inadequate	\N	CYP2D6*137 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 50.1% and 78.2% 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
8232374	2	CYP2D6	*13+*1	\N	Normal function	\N	1.0	8232373	{}	\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
777985	400	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
777995	400	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
778017	400	CYP2D6	*42	\N	No function	\N	0.0	778016	{12811367}	Limited	\N	CYP2D6*42 is assigned no function based on limited evidence in a heterozygous subject. CYP2D6*42 has been described in subjects with CYP2D6 *17/*42 genotype demonstrating decreased metabolism and a subject with CYP2D6 *40/*42 genotype demonstrating poor metabolism with a dextromethorphan substrate (12811367). CYP2D6*42 is defined by a base pair insertion resulting in a frameshift 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": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.00077314815, "Sub-Saharan African": 0.001, "African American/Afro-Caribbean": 0.0036646896}	f
778063	400	CYP2D6	*65	\N	Uncertain function	\N	n/a	778062	{24647041,30366777}	Inadequate	\N	CYP2D6*65 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*65 demonstrated decreased enzyme activity compared to wildtype with various substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.029529046, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
8232375	2	CYP2D6	*13+*1x2	\N	Increased function	\N	2.0	8232373	{}	\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
8232377	2	CYP2D6	*13+*2	\N	Normal function	\N	1.0	8232376	{}	\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
8232379	2	CYP2D6	*13+*68x2+*4	\N	No function	\N	0.0	8232378	{}	\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
8232372	2	CYP2D6	*36+*10	\N	Decreased function	\N	0.25	8232371	{}	\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
8232381	2	CYP2D6	*36x2+*10	\N	Decreased function	\N	0.25	8232380	{}	\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
8232370	2	CYP2D6	*68+*4	\N	No function	\N	0.0	8232369	{}	\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
778328	241	DPYD	Reference	Normal function	Normal function	\N	1.0	778327	{38129972}	\N	\N	Individual patients have been reported (PMID 38129972) to carry only one of the two SNPs in the HapB3 haplotype (i.e., c.1236G>A without c.1129-5923C>G), suggesting that the two variants are not in complete linkage disequilibrium. To address this, c.1129-5923C>G SNP is listed separately as this is likely the causal variant leading to decreased function. The HapB3 haplotype definition was also retained for cases where only the c.1236G>A variant is tested (e.g. whole exome sequencing). While CPIC recommends to directly test the causal SNP if possible, in cases where only c.1236G>A is tested or results are available for, it should be clearly stated in the test report that "decreased function" was inferred by detecting the exonic tag SNP, and disclose that in rare cases, the causal decreased function variant c.1129-5923C>G may not be present despite having this tag SNP.	\N	f
778851	356	G6PD	Wexham	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778850	{22293322,7577654}	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
3685375	195	RYR1	c.680A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685374	{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
3685499	195	RYR1	c.4763C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685498	{35849058}	\N	\N	None	{"Latino": null, "European": 0.0000703, "East Asian": 0.0000714, "Near Eastern": null, "Central/South Asian": 0.0000118, "Sub-Saharan African": 0.0001355}	f
778003	400	CYP2D6	*35	\N	Normal function	\N	1.0	778002	{9241659,12766015,21833166,24647041,30366777}	Moderate	\N	CYP2D6*35 is assigned normal function based on moderate evidence in heterozygous subjects. CYP2D6*35 was first identified in a subject with CYP2D6*5/*35 genotype demonstrating similar dextromethorphan metabolism compared to CYP2D6 *1/*5 subjects, indicating normal function of the CYP2D6*35 allele (9241659). Similarly, a subject with CYP2D6*4/*35 genotype demonstrated decreased dextromethorphan metabolism compared to wildtype subjects (21833166). Additionally, a study of 396 subjects found the -1584C>G substitution, which is found in CYP2D6*35 and other normal function alleles such as CYP2D6*2, was not observed in any subject demonstrating poor dextromethorphan metabolism, indicating normal function of the CYP2D6*35 allele (12766015). Although two in vitro studies found CYP2D6*35 had decreased enzyme activity compared to wildtype (24647041, 30366777), experts did not find these results convincing as the expression system may not be reflective of in vivo environment as demonstrated by the numerous subjects carrying the CYP2D6*35 allele with substrate metabolism similar to that of wildtype as described previously. Therefore, consensus among experts was normal function with an activity value of 1 based on moderate evidence.	{"Latino": 0.026583293, "American": 0.011335291, "European": 0.05468046, "Oceanian": 0.003691906, "East Asian": 0.0005036332, "Near Eastern": 0.022185262, "Central/South Asian": 0.008267974, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.008867127}	f
778739	356	G6PD	Bao Loc	II/Deficient	II/Deficient	\N	\N	778738	{22293322,17726510}	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
779019	356	G6PD	Flores	II/Deficient	II/Deficient	\N	\N	779018	{22293322,15065213}	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
778819	356	G6PD	Harilaou	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778818	{22293322,2222408}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.00003647638, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778693	356	G6PD	Kamogawa	II/Deficient	II/Deficient	\N	\N	778692	{22293322,9410474}	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
778849	356	G6PD	La Jolla	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778848	{22293322,12064902}	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
778785	356	G6PD	Naone	II/Deficient	II/Deficient	\N	\N	778784	{22293322,11852882}	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
778707	356	G6PD	Songklanagarind	II/Deficient	II/Deficient	\N	\N	778706	{22293322,15727905}	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
778965	356	G6PD	Utrecht	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778964	{22293322,14757426}	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
3685485	195	RYR1	c.3656A>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685484	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778336	389	DPYD	c.85T>C (*9A)	Normal function	Normal function	\N	1.0	778335	{18452418}	Strong	\N	Dihydrouracil (in vivo)	{"Latino": 0.20892397, "European": 0.22749932, "East Asian": 0.076328315, "Central/South Asian": 0.25525716, "Sub-Saharan African": 0.4464008, "African American/Afro-Caribbean": 0.42713377}	f
778490	385	DPYD	c.3061G>C	Normal function	Normal function	\N	1.0	778489	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000090985195, "East Asian": 0.0, "Central/South Asian": 0.00010, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778841	356	G6PD	Cleveland Corum	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778840	{22293322,7803800,7577654}	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
778727	356	G6PD	Guangzhou	III/Deficient	III/Deficient	\N	\N	778726	{22293322,16607506}	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
779017	356	G6PD	Kamiube, Keelung	III/Deficient	III/Deficient	\N	\N	779016	{22293322,511159,9192788,9444913}	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
778933	356	G6PD	Madrid	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778932	{22293322,9332310}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
779153	383	RYR1	c.130C>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	779152	{33767344}	\N	\N	PS3_Mod, PS4_Mod, PM1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778207	306	CYP2D6	*144	\N	No function	\N	0.0	778206	{33998274}	Limited	\N	CYP2D6*144 is assigned no function based on limited evidence. CYP2D6*144 is defined by a splice accepter variant predicting abberant splicing. 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. Two subjects genotyped as *1/*144 and *2/*144 had ratios comparable to that of subjects with an AS of 1 (33998274). Therefore, consensus among experts was no 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": 0.0, "African American/Afro-Caribbean": 0.0}	f
4058605	107	CYP4F2	*17	\N	\N	\N	\N	4058604	\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
778414	387	DPYD	c.1601G>A (*4)	Normal function	Normal function	\N	1.0	778413	{23588312}	Moderate	\N	5-fluorouracil (ex vivo)	{"Latino": 0.009438756, "European": 0.019760394, "East Asian": 0.0, "Central/South Asian": 0.008595228, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.009713376}	f
778931	356	G6PD	Lynwood	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778930	{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
778883	356	G6PD	Nara	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778882	{22293322,8241497}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
778981	356	G6PD	Surabaya	II/Deficient	II/Deficient	\N	\N	778980	{22293322,11499668}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.000036485697, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778919	356	G6PD	Tenri	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778918	{22293322}	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
778799	356	G6PD	Tsukui	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778798	{22293322,3360447}	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
778873	356	G6PD	West Virginia	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778872	{22293322,7803800}	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
777531	404	CYP2C19	*38	\N	Normal function	\N	\N	777530	{2009263,32602114}	Definitve	\N	CYP2C19*38 is assigned normal function based on definitive evidence. CYP2C19*38 was originally catalogued as CYP2C19*1.001 (i.e. CYP2C19*1A) (2009263). Due to the standardized nomenclature system this allele received its own star designation and is now catalogued as CYP2C19*38 (32602114). Therefore, because CYP2C19*38 does not contain any single nucleotide polymorphisms and the new star designation was a result of nomenclature standardization, consensus among experts was normal 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
778390	387	DPYD	c.1278G>T	Normal function	Normal function	\N	1.0	778389	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013647595, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778418	387	DPYD	c.1627A>G (*5)	Normal function	Normal function	\N	1.0	778417	{23328581}	Strong	\N	5-fluorouracil (in vitro)	{"Latino": 0.3070716, "European": 0.19492984, "East Asian": 0.25466427, "Central/South Asian": 0.09372777, "Sub-Saharan African": 0.157875, "African American/Afro-Caribbean": 0.14005096}	f
3827915	177	MT-RNR1	m.1537C>T	\N	uncertain risk of aminoglycoside-induced hearing loss	\N	\N	3827914	{17637808}	Inadequate evidence	\N	MT-RNR1 1537C>T 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 (17637808). Therefore, consensus among experts was uncertain risk of aminoglycoside-induced hearing loss due to insufficient evidence.	{"European": 0.00038541437, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null}	f
3827917	177	MT-RNR1	m.1555A>G	Conformational change to the mitochondrial 12s rRNA leading to binding of aminoglycoside antibiotics	increased risk of aminoglycoside-induced hearing loss	\N	\N	3827916	{7689389,8285309,8414970,9039999,9040738,9111378,9164619,9391883,9490575,9779807,9831149,9950117,10633132,10661905,11174959,11857751,11870684,12031626,12920080,14699607,14755216,15708009,15841390,15917167,16168391,16375862,16458854,16935512,16955413,17341440,17637808,17723226,17999439,18386806,18790089,18820594,18830133,19376484,19818876,19835846,20100600,20111055,20353758,21162657,21205314,21504270,22475488,23256547,24252789,25744662,26497601,27397648,27427311,29805548,24703164,25155176,8687424,9315872,12127547,19687236,28103015,10915767,12054632,21828074}	Definitive	\N	MT-RNR1 1555A>G is assigned an increased risk of aminoglycoside-induced hearing loss based on definitive evidence. Screening of individuals or probands of individuals with aminoglycoside-hearing loss identified 1494C>T in a number of cases (7689389, 8285309, 8414970, 9039999, 9040738, 9111378, 9164619, 9391883, 9490575, 9779807, 9831149, 9950117, 10633132, 10661905, 11174959, 11857751, 11870684, 12031626, 12920080, 14699607, 14755216, 15708009, 15841390, 15917167, 16168391, 16375862, 16458854, 16935512, 16955413, 17341440, 17637808, 17723226, 17999439, 18386806, 18790089, 18820594, 18830133, 19376484, 19818876, 19835846, 20100600, 20111055, 20353758, 21162657, 21205314, 21504270, 22475488, 23256547, 24252789, 25744662, 26497601, 27397648, 27427311, 29805548, 24703164, 25155176). There is inhibiton of translation in fibroblasts and cybrid cell lines with 1555A>G mutation (8687424). Aminoglycosides bind to 12S rRNA carrying the G allele, but not to rRNA with the A allele (9315872, 12127547, 19687236, 28103015). LCLs with the 1555A>G mutation have reduced growth and translation when grown in paromomycin (10915767). No effect of 1555A>G mutation in fibroblast lines. Cybrids with 1555A>G had slower growth in neomycin or paromomycin (12054632, 21828074). Therefore, consensus among experts was this variant is associated with increased risk of aminoglycoside-induced hearing loss based on definitive evidence.	{"European": 0.0011348277, "East Asian": 0.018102558, "Near Eastern": 0.0014195286, "Central/South Asian": 0.0011089911, "Sub-Saharan African": 0.0030045942}	f
3827919	177	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
777719	404	CYP2C9	*26	Decreased function	Decreased function	\N	0.5	777718	{23752738,19541829,16788382}	Limited	\N	CYP2C9*26 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*26 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": 0.002, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777773	404	CYP2C9	*53	Uncertain function	Uncertain function	\N	n/a	777772	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25951663,25924705,27163851,23844998}	Inadequate evidence	\N	CYP2C9*53 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2C9*53 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
778197	399	CYP2D6	*139	\N	Unknown function	\N	n/a	778196	{}	No Evidence	\N	CYP2D6*139 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": 0.001, "Sub-Saharan African": 0.001, "African American/Afro-Caribbean": 0.0}	f
3685399	195	RYR1	c.1144C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685398	{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
777485	404	CYP2B6	*33	\N	Uncertain function	\N	\N	777484	{23418033,30201214}	Inadequate	\N	CYP2B6*33 (c.1459C>A, p.R487S) – Uncertain function: CYP2B6*33 is assigned uncertain function. In vitro studies using cDNA expression systems found CYP2B6*33 demonstrated activity similar to the *1 reference or increased enzyme activity (23418033, 30201214). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was uncertain function based on inadequate evidence as it could not be determined if phenotypes containing this allele would be clinically distinct from phenotypes comprising 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
778133	399	CYP2D6	*107	\N	Unknown function	\N	n/a	778132	{}	No Evidence	\N	CYP2D6*107 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
778486	385	DPYD	c.2983G>T (*10)	No function	No function	\N	0.0	778485	{24648345}	Moderate	\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
777729	404	CYP2C9	*31	Decreased function	Decreased function	\N	0.5	777728	{23752738,24118918,23844998,25142737,25144335,25951663,25476996,25832633,25884291,25924705,27163851,27199745,24077631}	Limited	\N	CYP2C9*31 is assigned decreased function based on limited evidence. Multiple in vitro studies using different cell systems found CYP2C9*31 demonstrated decreased clearance for numerous substrates compared to wildtype (23752738, 24118918, 23844998, 25144335, 25951663, 25476996, 25832633, 25884291, 27163851, 25924705, 27199745, 24077631). Although one in vitro study showed CYP2C9*31 had similar activity compared to wildtype, the experts did not find this result convincing as in this study CYP2C9*2 and CYP2C9*3 which definitively have decreased function and no function, respectively, demonstrated increased activity compared to wildtype (25142737). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0016030075, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779694	330	CYP2D6	*3x2	\N	No function	\N	0.0	777940	{2211621}	Limited	\N	CYP2D6*3x2 is assigned no function based on limited evidence. CYP2D6*3 is defined by a single nucleotide deletion causing a frameshift and resulting in a nonfunctional protein and is assigned no function (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 a duplication of this allele would be clinically similar to phenotypes comprising the nonduplicated allele.	{"Latino": 0.00050, "American": null, "European": 0.00010, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778995	356	G6PD	Cassano	II/Deficient	II/Deficient	\N	\N	778994	{22293322,8447319,10782016}	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
777711	404	CYP2C9	*22	Uncertain function	Uncertain function	\N	n/a	777710	{23752738}	Inadequate evidence	\N	CYP2C9*22 is assigned uncertain function due to inadequate evidence. In one in vitro study, CYP2C9*22 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": 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
778103	400	CYP2D6	*92	\N	No function	\N	0.0	778102	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Limited	\N	CYP2D6*92 is assigned no function based on limited evidence. Multiple in vitro studies found CYP2D6*92 had nondetectable enzyme with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). CYP2D6*92 is defined by a deletion resulting in a frameshift and early stop codon and 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
2091243	304	CYP2D6	*155	\N	Unknown function	\N	n/a	2091242	{}	No Evidence	\N	CYP2D6*155 is assigned unknown function due to no literature describing function of this allele. CYP2D6*155 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": 0.00104, "African American/Afro-Caribbean": null}	f
778771	356	G6PD	Ilesha	III/Deficient	III/Deficient	\N	\N	778770	{22293322,7959686,848857}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0011765126, "European": 0.000009013232, "East Asian": 0.0, "Central/South Asian": 0.00041928721, "African American/Afro-Caribbean": 0.00052700925}	f
6481207	42	NAT2	*16	Slow	Decreased function	\N	\N	6481206	{9154882,28653770,30564082,15558239,7668286,10744128,9333101,17011540,9321764,11214777,27509179,20801937,9891107,9565293,9682266,24221535,8923605,10762005,28752039,21946899,15564878,7669073,10574910,15564878}	Definitive	\N	NAT2*16 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*16 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*16 is characterized by the core SNVs c.341T>C (p.I114T) 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.341T>C (p.I114T) in NAT2*16 has been studied for more than 25 years and has shown decreased NAT2 N-acetylation in numerous clinical studies using caffeine (7668286, 9333101, 9891107, 10744128, 20801937, 24221535), sulfamethazine (21946899), dapsone (10762005), or isoniazid (9321764) as a substrate. Five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C impairs protein function. An in vitro study using a bacterial expression system measured the N-acetyltransferase capacity of a NAT2 construct containing the SNVs c.341T>C (p.I114T) and c.481C>T (p.L161=) and found this enzyme exhibited decreased activity compared to the former reference NAT2*4, using either 2-aminofluorene or sulfamethazine as substrates (7669073 ). Another in vitro study using a yeast expression system found that NAT2*16 displayed decreased thermostability relative to the former reference NAT2*4 resulting in decreased N-acetylation activity toward sulfamethazine (10574910). NAT2*16 was also shown to have decreased N-acetyltransferase activity in human hepatocytes (genotyped as NAT2*4/*16 or NAT2*6/*16) using isoniazid as a substrate (28752039). 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*16 would presumably be degraded in the same manner.	\N	f
3685527	195	RYR1	c.6037A>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685526	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778145	399	CYP2D6	*113	\N	Uncertain function	\N	n/a	778144	{31368850}	Inadequate	\N	CYP2D6*113 is assigned uncertain function. CYP2D6*113 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": 0.0, "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
2784577	174	CYP4F2	*6	\N	\N	\N	\N	2784576	\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
2784579	174	CYP4F2	*7	\N	\N	\N	\N	2784578	\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
3318586	145	CYP4F2	*8	\N	\N	\N	\N	3318585	\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
778360	391	DPYD	c.775A>G	Normal function	Normal function	\N	1.0	778359	{25410891}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.007314514, "European": 0.015303651, "East Asian": 0.0, "Central/South Asian": 0.0068804934, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0030573248}	f
778382	387	DPYD	c.1180C>T	Normal function	Normal function	\N	1.0	778381	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.00010, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778396	387	DPYD	c.1349C>T	Normal function	Normal function	\N	1.0	778395	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.00008888889, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.003892857, "African American/Afro-Caribbean": 0.0}	f
778823	356	G6PD	Mexico City	III/Deficient	III/Deficient	\N	\N	778822	{22293322,1611091}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.00018234865, "European": 0.000040952138, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778855	356	G6PD	Chinese-1	II/Deficient	II/Deficient	\N	\N	778854	{22293322,1459579}	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
778675	356	G6PD	Gaohe	III/Deficient	III/Deficient	\N	\N	778674	{22293322,1945893}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0019558913, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
777559	404	CYP2C19	*14	\N	Uncertain function	\N	\N	777558	{21325430,25001882,21692664}	Inadequate	\N	CYP2C19*14 is assigned uncertain function due to inadequate evidence. CYP2C19*14 demonstrated similar enzyme activity compared to wildtype with mephenytoin, omeprazole, and other substrates (21325430, 21692664). In a separate in vitro study CYP2C19*14 demonstrated decreased activity compared to wildtype with mephenytoin and clopidogrel substrates (25001882). Therefore, consensus among experts was not achieved and uncertain function was assigned.	{"Latino": 0.0, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0001145213, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778376	387	DPYD	c.1108A>G	Normal function	Normal function	\N	1.0	778375	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.00028279895, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
3942828	174	DPYD	c.1129-5923C>G	Decreased function	Decreased function	\N	0.5	3942827	{28295243}	Strong	\N	5-fluorouracil (ex vivo)	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778953	356	G6PD	Bari	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778952	{22293322,8808605,7959695}	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
3685357	195	RYR1	c.526G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685356	{35849058}	\N	\N	PS4_Mod, PM1	{"Latino": null, "European": 0.0000254, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.000022, "Sub-Saharan African": 0.0000267}	f
1406322	386	CYP2C9	*75	Unknown function	Unknown function	\N	n/a	1406321	{}	No evidence	\N	CYP2C9*75 is assigned unknown function due to no literature describing function of this allele. Therefore, consensus among experts was unknown function due to no available evidence.	{"Latino": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778845	356	G6PD	Bangkok	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778844	{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
778364	391	DPYD	c.929T>C	Normal function	Normal function	\N	1.0	778363	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013648342, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778089	399	CYP2D6	*85	\N	Unknown function	\N	n/a	778088	{}	No Evidence	\N	CYP2D6*85 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": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778350	391	DPYD	c.525G>A	Normal function	Normal function	\N	1.0	778349	{23588312}	Limited	\N	5-fluorouracil (ex vivo)	{"Latino": 0.00014510652, "European": 0.0, "East Asian": 0.000081102364, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0019642857, "African American/Afro-Caribbean": 0.0}	f
777595	404	CYP2C19	*35	\N	No function	\N	\N	777594	{26021325}	Limited	\N	CYP2C19*35 is assigned no function based on limited evidence. CYP2C19*35 is defined by a splicing defect resulting in a truncated protein (26021325). This splicing defect is also found in CYP2C19*2 which definitively has no function. Although subjects with CYP2C19 *1/*35 did not demonstrate significantly decreased enzyme activity compared to wildtype based on urine metabolites after mephenytoin 100mg once (26021325), the experts did not find this result convincing due to the small sample size. Therefore, consensus among experts was no function based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function and decreased function alleles.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.032099508, "African American/Afro-Caribbean": 0.015904458}	f
778448	385	DPYD	c.2186C>T	Normal function	Normal function	\N	1.0	778447	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.00001364734, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778743	356	G6PD	Acrokorinthos	II/Deficient	II/Deficient	\N	\N	778742	{22293322,32387609,15223006,2393028}	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
777701	404	CYP2C9	*17	Uncertain function	Uncertain function	\N	n/a	777700	{23752738,16099926}	Inadequate evidence	\N	CYP2C9*17 is assigned uncertain function based on inadequate evidence due to conflicting in vitro data and no clinical data. In an in vitro study CYP2C9*17 demonstrated 32% 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, 16099926). 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": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685501	195	RYR1	c.4775C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685500	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": 0.000006938, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.0000118, "Sub-Saharan African": 0.0000136}	f
3685509	195	RYR1	c.5132A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685508	{35849058}	\N	\N	PS4_Sup, PP1_Sup, PS3_Mod	{"Latino": null, "European": 0.0000178, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000534}	f
6481209	42	NAT2	*19	Slow	Decreased function	\N	\N	6481208	{18680467,12222688,9173883}	Limited	\N	NAT2*19 is assigned decreased function based on limited evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the NAT2*19 allele as "slow" . Under the CPIC allele function terminology, slow acetylation alleles are categorized as "Decreased Function". NAT2*19 is characterized by the core SNVs c.190C>T (p.R64W) and c.803G>A (p.R268K). c.803G>A defines NAT2*4, formerly considered the reference allele, which has repeatedly exhibited increased function in vivo and in vitro. In vitro studies of c.190C>T (p.R64W) have shown decreased protein expression, decreased thermostability, and significantly decreased N-acetyltransferase activity toward sulfamethazine (12222688). An additional in vitro study found that amino acid substitutions of arginine 64 to alanine, lysine, methionine, or glutamine (the latter of which defines NAT2*14) significantly decreased NAT2 protein stability and N-acetyltransferase activity toward p-aminosalicylic acid and all but p.R64K showed decreased N-acetyltransferase activity toward sulfamethazine (9173883). These results highlight the importance of the p.R64 residue for proper NAT2 catalytic activity. Published in silico modeling predicts that c.190C>T (p.R64W) decreases NAT2 protein stability, decreases flexibility and hydrogen bond capacity, and increases hydrophobicity and aromaticity resulting in a loss of electrostatic interactions (18680467). Similarly, six out of ten variant effect predictors tested by CPIC staff predict that c.190C>T (p.R64W) impairs NAT2 protein function.	\N	f
779734	331	CYP2D6	*36x2	\N	No function	\N	0.0	778004	{12439227}	Limited	\N	CYP2D6*36x2 is assigned no function based on limited evidence in a heterozygous subject. CYP2D6*36x2 has been described in a subject with CYP2D6*21/*36x2 genotype demonstrating poor metabolism with a debrisoquine substrate (12439227). 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": 0.00050, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.004052432, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.000092301394}	f
778366	391	DPYD	c.934C>T	Normal function	Normal function	\N	1.0	778365	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000013648715, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778398	387	DPYD	c.1358C>G	Normal function	Normal function	\N	1.0	778397	{23588312}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.002017857, "African American/Afro-Caribbean": 0.0030573248}	f
778402	387	DPYD	c.1403C>A	Normal function	Normal function	\N	1.0	778401	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000039617094, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778426	385	DPYD	c.1775G>A	No function	No function	\N	0.0	778425	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778751	356	G6PD	A- 968C_376G	III/Deficient	III/Deficient	\N	\N	778750	{22293322,32387609,2572288}	strong	\N	Function assigned based on the WHO recommendations included in PMID 22293322. Additional in vitro (32387609) and the presence of this variant in G6PD deficient males (2572288) supports this classificaiton.	{"Latino": 0.0007489835, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0054458817}	f
778741	356	G6PD	Crispim	II/Deficient	II/Deficient	\N	\N	778740	{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
6481229	42	NAT2	*36	Slow	Decreased function	\N	\N	6481228	{}	Moderate	\N	NAT2*36 is assigned decreased function based on moderate evidence. NAT2*36 is characterized by the core SNVs c.403C>G (p.L135V), 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.403C>G (p.L135V). Ten out of ten variant effect predictors tested by CPIC staff predict that c.403C>G is neutral/tolerated for 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 impairs protein function. Thus, NAT2*36 is assigned decreased function based on c.590G>A. While c.403C>G is not predicted to impair protein function, it remains unknown whether there are any combinatorial effects associated with c.590G>A and c.403C>G.	\N	f
6481255	42	NAT2	*49	Slow	Decreased function	\N	\N	6481254	{19909761}	Moderate	\N	NAT2*49 is assigned decreased function based on moderate evidence. NAT2*49 is characterized by the core SNVs c.341T>C (p.I114T) and c.578C>T (p.T193M). Published in silico modeling predicts that c.578C>T (p.T193M) impairs protein function based on exposure of hydrophobic residues that may facilitate protein aggregation or targeted degradation (19909761). Similarly, six out of ten variant effect predictors tested by CPIC staff predict that c.578C>T (p.T193M) impairs protein function. c.341T>C (p.I114T) defines NAT2*5 which has repeatedly shown decreased N-acetyltransferase activity in numerous in vivo and in vitro studies. Additionally, an in vitro study showed that NAT2*5 is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*49 would presumably be degraded in the same manner. Five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. Thus, NAT2*49 is assigned decreased function based on c.341T>C. Despite this, it remains unknown whether there are any combinatorial effects associated with c.341T>C and c.578C>T	\N	f
7096547	28	NAT2	*67	Slow	Decreased function	\N	\N	7096546	{29273096}	Moderate	\N	NAT2*67 is assigned decreased function based on moderate evidence. NAT2*67 is characterized by the core SNVs c.590G>A (p.R197Q), c.803G>A (p.R268K), and c.823T>A (p.L275M). 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.823T>A (p.L275M). Five out of ten variant effect predictors tested by CPIC staff predict c.823T>A (p.L275M) impairs protein function, which is supported by published in silico analysis (29273096). c.590G>A (p.R197Q) defines NAT2*6 which has been extensively studied, exhibiting decreased N-acetyltransferase activity both in vivo and in vitro. Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that c.590G>A (p.R197Q) impairs protein function. Thus, NAT2*67 is assigned decreased function based on c.590G>A. Despite this, the combinatorial effects associated with c.823T>A and c.590G>A are uncertain.	\N	f
778779	356	G6PD	Plymouth	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778778	{22293322,7577654}	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
778432	385	DPYD	c.1896T>C	Normal function	Normal function	\N	1.0	778431	{23588312}	Moderate	\N	5-fluorouracil (ex vivo)	{"Latino": 0.08113257, "European": 0.03787994, "East Asian": 0.12373856, "Central/South Asian": 0.03587631, "Sub-Saharan African": 0.007970238, "African American/Afro-Caribbean": 0.03187898}	f
778434	385	DPYD	c.1898delC (*3)	No function	No function	\N	0.0	778433	{24648345}	Moderate	\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
7096551	28	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
777949	400	CYP2D6	*7	\N	No function	\N	0.0	777948	{7845481,24647041,30366777}	Limited	\N	CYP2D6*7 is assigned no function based on limited evidence. CYP2D6*7 was first described in subjects demonstrating decreased sparteine metabolism (7845481). Two in vitro studies found CYP2D6*7 had nondetectable or markedly decreased enzyme activity compared to wildtype with tamoxifen, bufuralol, dextromethorphan, and primaquine substrates (24647041, 30366777). CYP2D6*7 is defined by an amino substitution near the active site disrupting protein folding and resulting in a nonfunctional enzyme based on computational analysis (7845481). 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": 0.0030718232, "European": 0.0005116425, "Oceanian": 0.0, "East Asian": 0.000073912495, "Near Eastern": 0.00286119, "Central/South Asian": 0.0073079397, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0002489224}	f
778404	387	DPYD	c.1475C>T	No function	No function	\N	0.0	778403	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.00020, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6481223	42	NAT2	*33	Slow	Decreased function	\N	\N	6481222	{19164093,19909761,15564878}	Moderate	\N	NAT2*33 is assigned decreased function based on moderate evidence. NAT2*33 is characterized by the core SNVs c.341T>C (p.I114T, defining NAT2*5) and c.472A>C (p.I158L). Published in silico modeling predicts that c.472A>C (p.I158L) does not alter NAT2 protein function (19164093, 19909761). Similarly, ten out of ten variant effect predictors tested by CPIC staff predict that c.472A>C (p.I158L) is neutral/tolerated for NAT2 function. Thus, NAT2*33 is assigned decreased function based on c.341T>C (p.I114T) . c.341T>C (p.I114T) defines NAT2*5 which has repeatedly shown decreased NAT2 function in numerous in vivo and in vitro studies. Additionally, an in vitro study showed that NAT2*5 is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*33 would presumably be degraded in the same manner. Five out of ten variant effect predictors tested by CPIC staff predict that c.341T>C (p.I114T) impairs protein function. While.472A>C is not predicted to impair protein function, it remains unknown whether there are any combinatorial effects associated with c.341T>C and c.472A>C.	\N	f
777957	400	CYP2D6	*11	\N	No function	\N	0.0	777956	{8563771,9241659}	Limited	\N	CYP2D6*11 is assigned no function based on limited evidence. CYP2D6*11 is defined by a splicing defect yielding a nonfunctional enzyme and was identified in a subject demonstrating markedly decreased sparteine metabolism (8563771, 9241659). 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": 0.0, "European": 0.000148423, "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": 0.00028528165}	f
7219571	26	NAT2	*70	Slow	Decreased function	\N	\N	7219570	{15564878,35588539}	Limited	\N	NAT2*70 is assigned decreased function based on moderate evidence. An individual heterozygous for NAT2*70 experienced drug-induced hepatotoxicity after standard isoniazid dosing (35588539). NAT2*70 is defined by the core SNVs c.341T>C (p.I114T) and c.596T>C (p.I199T). 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*70 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. Three out of ten variant effect predictors tested by CPIC staff predict that c.596T>C (p.I199T) impairs protein function. NAT2*70 is assigned decreased function based on c.341T>C. Despite this, the combinatorial effects associated with c.341T>C and c.596T>C are uncertain.	\N	f
778139	399	CYP2D6	*110	\N	Uncertain function	\N	n/a	778138	{31368850}	Inadequate	\N	CYP2D6*110 is assigned uncertain function. CYP2D6*110 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": 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
3685365	195	RYR1	c.533A>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685364	{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
6481231	42	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
777979	400	CYP2D6	*23	\N	Uncertain function	\N	n/a	777978	{24647041,30366777}	Inadequate	\N	CYP2D6*23 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*23 demonstrated modest 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 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": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778358	389	DPYD	c.703C>T (*8)	No function	No function	\N	0.0	778357	{24648345}	Moderate	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.00009098349, "East Asian": 0.0, "Central/South Asian": 0.00020, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778370	387	DPYD	c.1003G>T (*11)	Normal function	Normal function	\N	1.0	778369	{24648345}	Moderate	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.00010, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
6481247	42	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	42	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
7219579	26	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
2899157	193	CYP2B6	*46	\N	Uncertain function	\N	\N	2899156	{38596098}	Inadequate	\N	CYP2B6*46 (c.740A>C, p.H247P) – Uncertain function: CYP2B6*46 is assigned uncertain function due to inadequate evidence describing function. A single in vitro study reported decreased function for p.H247P 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
777675	404	CYP2C9	*4	Decreased function	Decreased function	\N	0.5	777674	{23752738,21228733}	Limited	\N	CYP2C9*4 is assigned decreased function based on limited evidence in heterozygous patients and in vitro studies. One patient on a stable dose of warfarin with CYP2C9*1/*4 genotype required a lower weekly warfarin dose compared to CYP2C9*1/*1 patients (21228733). In an in vitro study CYP2C9*4 demonstrated 16% enzyme activity with a warfarin substrate and 22% enzyme activity with a tolbutamide substrate compared to wildtype. The CYP2C9*4 defining SNP occurs in the substrate recognition site which likely contributes to the loss of enzyme activity (23752738). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.0, "American": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0011754684, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778061	400	CYP2D6	*64	\N	Uncertain function	\N	n/a	778060	{24647041,30366777}	Inadequate	\N	CYP2D6*64 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*64 demonstrated decreased enzyme activity compared to wildtype with various substrates (24647041, 30366777). Consensus was not achieved among experts as data were sparse. Therefore, uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": null}	f
6235906	47	CYP4F2	*18	\N	\N	\N	\N	6235905	\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
778388	387	DPYD	c.1260T>A	Normal function	Normal function	\N	1.0	778387	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0005544641, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778492	385	DPYD	c.3067C>A	Normal function	Normal function	\N	1.0	778491	{23588312}	Limited	\N	5-fluorouracil (ex vivo)	{"Latino": 0.00089275226, "European": 0.000013283348, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.034825396, "African American/Afro-Caribbean": 0.044617835}	f
3685359	195	RYR1	c.528G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685358	{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
6481285	42	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
779688	334	CYP2D6	*1x2	\N	Increased function	\N	2.0	777936	{7616439,9012401}	Limited	\N	CYP2D6*1x2 is assigned increased function based on limited evidence. Subjects with CYP2D6 gene duplications demonstrated increased enzyme activity with the greatest debrisoquine metabolism among 270 subjects based on urine metabolites (7616439). Additionally, debrisoquine metabolism correlated with the number of functional CYP2D6 genes (7616439, 9012401). Therefore, consensus among experts was increased function with an activity value of 2 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.015091962, "American": 0.025994705, "European": 0.008242789, "Oceanian": 0.118886255, "East Asian": 0.0033543645, "Near Eastern": 0.031482305, "Central/South Asian": 0.005793713, "Sub-Saharan African": 0.0057788896, "African American/Afro-Caribbean": 0.007974796}	f
778077	399	CYP2D6	*74	\N	Unknown function	\N	n/a	778076	{}	No Evidence	\N	CYP2D6*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": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0013710798, "African American/Afro-Caribbean": 0.0}	f
778099	400	CYP2D6	*90	\N	Uncertain function	\N	n/a	778098	{25469868,26310775,26666748,26544071,26406933,27109434,27097346,27016952,26542054,26937172,26968424,27203132,27251229,27354764,27538917}	Inadequate	\N	CYP2D6*90 is assigned uncertain function due to inadequate evidence. In vitro studies found CYP2D6*90 demonstrated enzyme activity ranging from increased to decreased activity compared to wildtype with various substrates (25469868, 26310775, 26666748, 26544071, 26406933, 27109434, 27097346, 27016952, 26542054, 26937172, 26968424, 27203132, 27251229, 27354764, 27538917). Therefore, consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685529	195	RYR1	c.6178G>T	Benign	Normal function	\N	n/a	3685528	{33767344}	\N	\N	BA1	{"Latino": 0.0680311, "European": 0.06505523, "East Asian": 0.0062391, "Near Eastern": 0.09177833, "Central/South Asian": 0.1533597, "Sub-Saharan African": 0.0124217}	f
778195	400	CYP2D6	*138	\N	Uncertain function	\N	n/a	778194	{31536170}	Inadequate	\N	CYP2D6*138 is assigned uncertain function due to inadequate evidence. CYP2D6*138 is defined by a splice defect known to decrease activity and an amino acid substitution which an in vitro study found to increase activity compared to *1 when expressed on its own (31536170). 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
778243	226	CYP4F2	*3	\N	\N	\N	\N	778242	\N	\N	\N	\N	{"Latino": 0.25830573, "American": 0.4107687, "European": 0.27461374, "East Asian": 0.23247077, "Near Eastern": 0.35087985, "Central/South Asian": 0.40285128, "Sub-Saharan African": 0.09881758, "African American/Afro-Caribbean": 0.07623351}	f
778368	391	DPYD	c.967G>A	Normal function	Normal function	\N	1.0	778367	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000041703854, "East Asian": 0.0, "Central/South Asian": 0.00017881511, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778436	385	DPYD	c.1905C>G	Normal function	Normal function	\N	1.0	778435	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.000054979286, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778446	385	DPYD	c.2161G>A	Normal function	Normal function	\N	1.0	778445	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.00023592282, "European": 0.0001946586, "East Asian": 0.0, "Central/South Asian": 0.000089406414, "Sub-Saharan African": 0.0009821429, "African American/Afro-Caribbean": 0.0}	f
778903	356	G6PD	Mira d'Aire	IV/Normal	IV/Normal	\N	\N	778902	{22293322,1945893}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.00060634164, "European": 0.000009038323, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.00037544584}	f
6481251	42	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
777785	404	CYP2C9	*59	Decreased function	Uncertain function	\N	n/a	777784	{25142737,25994031,25884291}	Inadequate evidence	\N	CYP2C9*59 is assigned uncertain function due to inadequate evidence. CYP2C9*59 was first described in a patient requiring a low daily warfarin dose of 1.5mg (25994031). No variant was observed in VKORC1 or CYP4F2 in this patient and a subsequent in silico study showed destabilization of the interaction with the heme group may cause reduction in catalytic activity in this allele. In vitro studies found CYP2C9*59 demonstrated decreased enzyme activity with multiple substrates (25142737, 25994031, 25884291). 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
779703	330	CYP2D6	*9x2	\N	Decreased function	\N	0.5	777952	{1844820,8101460,11266079,24647041,30366777}	Limited	\N	CYP2D6*9x2 is assigned decreased function based on limited evidence. CYP2D6*9 is assigned decreased function based on decreased protein expression and enzyme activity (1844820, 8101460, 11266079, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing a duplication of this allele would demonstrate greater protein expression and enzyme activity than that of the nonduplicated allele and be clinically similar to phenotypes comprising decreased function alleles.	{"Latino": 0.0, "American": 0.0, "European": 0.000111773355, "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
778354	391	DPYD	c.601A>C	No function	No function	\N	0.0	778353	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.00004094045, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778811	356	G6PD	Dagua	Uncertain	Uncertain function	\N	\N	778810	{22293322}	Inadequate	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.000104821804, "African American/Afro-Caribbean": 0.0}	f
6481191	42	NAT2	*1	Rapid	Increased function	\N	\N	6481190	{9154882,30564082,15558239,10744128,22092036,20040334,9333101,17011540,24444407,20801937,24221535,27223070,10762005,21946899}	Definitive	\N	NAT2*1 is assigned increased function based on definitive evidence. The NAT gene nomenclature committee has historically assigned acetylation activity to alleles as either "rapid" or "slow", classifying the reference NAT2*1 allele as "rapid". Under the CPIC allele function terminology, rapid acetylation alleles are categorized as "Increased Function". NAT2*1 corresponds to the NCBI reference sequence, NG_012246.1, containing no SNVs. NAT2*1 has been studied for more than 25 years and has shown rapid acetylation in numerous clinical studies with various substrates. Rapid acetylation activity has been demonstrated in individuals heterozygous for NAT2*1 using caffeine (9333101, 10744128, 15558239, 20801937, 24221535, 27223070), dapsone (10762005), sulfamethazine (21946899), and isoniazid (30149019). NAT2*1 is distinguished from NAT2*4 by the absence of the core SNV c.803G>A (p.R268K).	\N	t
777795	386	CYP2C9	*64	Uncertain function	Uncertain function	\N	n/a	777794	{33536773}	Inadequate evidence	\N	CYP2C9*64 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variants present in CYP2C9*64 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
778400	387	DPYD	c.1371C>T	Normal function	Normal function	\N	1.0	778399	{23588312}	Limited	\N	5-fluorouracil (ex vivo)	{"Latino": 0.00071320933, "European": 0.00017700421, "East Asian": 0.0, "Central/South Asian": 0.00008935568, "Sub-Saharan African": 0.020694444, "African American/Afro-Caribbean": 0.015828025}	f
778406	387	DPYD	c.1484A>G	No function	No function	\N	0.0	778405	{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
778121	400	CYP2D6	*101	\N	No function	\N	0.0	778120	{23394389}	Limited	\N	CYP2D6*101 is assigned no function based on limited evidence. CYP2D6*101 has been described in a subject with CYP2D6*2/*101 genotype demonstrating markedly decreased dextromethorphan metabolism compared to wildtype (23394389). CYP2D6*101 is defined by the same SNPs as CYP2D6*10 in addition to a 19 base pair deletion resulting in a frameshift yielding a nonfunctional protein. Therefore, consensus among experts was no function with an activity value of 0 based on limited evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": 0.003, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778420	387	DPYD	c.1679T>G (*13)	No function	No function	\N	0.0	778419	{23328581}	Moderate	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.00055783015, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
3685767	195	RYR1	c.9868G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685766	{35849058}	\N	\N	None	{"Latino": null, "European": 0.00000678, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000134}	f
777453	404	CYP2B6	*17	Normal function	Normal function	\N	\N	777452	{16272958,26655325,30201214,32238417,35538637}	Limited	\N	CYP2B6*17 (c.76A>T, p.T26S; c.83A>G, p.D28G; c.85C>A+c.86G>C, p.R29T) – Normal function: CYP2B6*17 is assigned normal function. A study evaluating efavirenz content in hair samples among HIV patients taking efavirenz for more than three months found that long term efavirenz exposure was not impacted by the CYP2B6*17 allele (26655325). Additionally, CYP2B6*17 had similar enzyme activity in vitro using cDNA expression systems compared to the *1 reference (16272958, 30201214, 32238417), but decreased activity for methadone (35538637). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was normal function based on limited evidence.	{"Latino": 0.0, "European": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0126, "African American/Afro-Caribbean": 0.071}	f
2899159	193	CYP2B6	*47	\N	Uncertain function	\N	\N	2899158	{38596098}	Inadequate	\N	CYP2B6*47 (c.1060_1061delinsCG, p.Y354R) – Uncertain function: CYP2B6*47 is assigned uncertain function due to inadequate evidence describing function. A single in vitro study reported decreased function for p.Y354R 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
6481193	42	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
6481203	42	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
778091	399	CYP2D6	*86	\N	Unknown function	\N	n/a	778090	{}	No Evidence	\N	CYP2D6*86 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": 0.0001941358, "Near Eastern": null, "Central/South Asian": 0.021387372, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
6481221	42	NAT2	*32	Slow	Decreased function	\N	\N	6481220	{1559981,9173883,19909761,15564878}	Moderate	\N	NAT2*32 is assigned decreased function based on moderate evidence. NAT2*32 is characterized by the core SNVs c.203G>A (p.C68Y) and c.341T>C (p.I114T). An in vitro study showed that substituting a glycine in place of cysteine at position p.68 abolished NAT2 N-acetyltransferase activity toward sulfamethazine, procainamide, p-aminosalicylic acid, and 2-aminofluorene; the authors discuss the high probability that p.Cys68 lies within the NAT2 active site and is directly involved in acetyl transfer (1559981). An additional in vitro study found that NAT2 p.C68A exhibited undetectable N-acetyltransferase activity toward p-aminosalicylic acid and sulfamethazine (9173883). Thus, substitution of a tyrosine in place of cysteine at residue p.68 would likely abolish NAT2 enzymatic activity. Published in silico modeling predicts that c.203G>A (p.C68Y) alters the NAT2 catalytic mechanism, rendering the protein non-functional (19909761). Lastly, nine out of ten variant effect predictors tested by CPIC staff predict that c.203G>A (p.C68Y) impairs protein function. c.341T>C (p.I114T) defines NAT2*5, which has repeatedly shown decreased NAT2 acetylation activity in numerous in vivo and in vitro studies. Additionally, an in vitro study showed that NAT2*5 is subjected to enhanced protein degradation by the proteasome (15564878). Thus, NAT2*32 would presumably be degraded in the same manner. While the committee agreed to the assignment of decreased function based on the function of c.341T>C (p.I114T), there was a lack of consensus regarding the function of c.203G>A (p.C68Y). It remains unknown whether there are any combinatorial effects associated with c.341T>C and c.203G>A.	\N	f
6481235	42	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
6481237	42	NAT2	*40	Slow	Decreased function	\N	\N	6481236	{28959610,17434923,18680467,11337936}	Definitive	\N	NAT2*40 is assigned decreased function based on definitive evidence. NAT2*40 is characterized by the core SNV c.857G>A (p.G286E, defining NAT2*7) which exhibits decreased N-acetylation activity toward sulfamethazine, decreased thermostability, and decreased protein expression in a mammalian cell lines compared to NAT2*4 (17434923). NAT2*40 also exhibits decreased protein levels when expressed in yeast cells (11337936). A clinical NAT2 phenotyping studying using isoniazid (INH) as a probe drug identified 2 patients carrying NAT2*40 (28959610). These individuals were classified among slow acetylators, who exhibited an acetylation index (defined as the ratio of plasma INH concentration at the 3rd hour, in mg/L + 0.6 divided by the dose in mg/kg) below that of rapid acetylators, which were defined as individuals homozygous for NAT2 increased function alleles *1 or *4 (28959610). Ten out of ten variant effect predictors tested by CPIC staff predict that c.857G>A (p.G286E) does not impair 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).	\N	f
777803	386	CYP2C9	*68	Uncertain function	Uncertain function	\N	n/a	777802	{33536773}	Inadequate evidence	\N	CYP2C9*68 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variants present in CYP2C9*68 are predicted to be deleterious in SIFT and and benign in Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777963	400	CYP2D6	*14	\N	Decreased function	\N	0.5	777962	{18784265,19364831,24647041,30366777}	Limited	\N	CYP2D6*14 is assigned decreased function based on limited evidence. Three subjects with CYP2D6*1/*14, CYP2D6 *10/*14, and CYP2D6*14/*41 genotype, respectively demonstrated decreased dextromethorphan metabolism compared to wildtype based on urine metabolites (19364831). Multiple in vitro studies found CYP2D6*14 had modestly decreased enzyme activity compared to wildtype with various substrates (18784265, 19364831, 24647041, 30366777). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on limited evidence as it was determined the phenotypes containing this allele would be clinically distinct from phenotypes comprising normal function alleles.	{"Latino": 0.0, "American": 0.0, "European": 0.0, "Oceanian": 0.0, "East Asian": 0.004713944, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0, "African American/Afro-Caribbean": 0.0}	f
778450	385	DPYD	c.2194G>A (*6)	Normal function	Normal function	\N	1.0	778449	{23328581}	Moderate	\N	5-fluorouracil (in vitro)	{"Latino": 0.027319003, "European": 0.044963934, "East Asian": 0.018249057, "Central/South Asian": 0.09505568, "Sub-Saharan African": 0.02695635, "African American/Afro-Caribbean": 0.016}	f
778452	385	DPYD	c.2195T>G	Normal function	Normal function	\N	1.0	778451	{24648345}	Limited	\N	5-fluorouracil (in vitro)	{"Latino": 0.0, "European": 0.0, "East Asian": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": 0.0019285714, "African American/Afro-Caribbean": 0.0}	f
6481253	42	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
7219581	26	NAT2	*75	Slow	Decreased function	\N	\N	7219580	{15564878}	Limited	\N	NAT2*75 is assigned decreased function based on moderate evidence. NAT2*75 is defined by the core SNVs c.264G>A (p.M88I) 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*75 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.264G>A. Ten out of ten variant effect predictors tested by CPIC staff predict that c.264G>A (p.M88I) is neutral for protein function. NAT2*75 is assigned decreased function based on c.341T>C. Despite this, the combinatorial effects associated with c.341T>C and c.264G>A are uncertain.	\N	f
777477	404	CYP2B6	*29	Decreased function	Decreased function	\N	\N	777476	{17885627,28181240}	Limited	\N	CYP2B6*29 (CYP2B7-CYP2B6 hybrid gene) – Decreased function: CYP2B6*29 is assigned decreased function. This allele is a hybrid consisting of CYP2B7 (exons 1-4) and CYP2B6 (exons 5-9) harboring 23 amino acid changes compared to the protein encoded by the CYP2B6*1 reference. Among those is c.516G>T which is one of the function-altering variants defining CYP2B6*6. CYP2B6*29 was identified in a subject with an elevated efavirenz AUC compared to the *1 reference and similar to those seen in patients carrying one decreased function allele (17885627). One in vitro study found that primary human hepatocytes of subjects with a CYP2B6*29 allele had slightly lower protein expression and enzyme activity compared to the *1 reference (28181240). The same study also showed that the AUC for 4-OH-cyclophosphamide was significantly lower for patients with a CYP2B6*1/*29 genotype compared to *1/*1 (28181240). Therefore, consensus among experts was decreased function based on limited evidence.	{"Latino": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777797	386	CYP2C9	*65	Uncertain function	Uncertain function	\N	n/a	777796	{33536773}	Inadequate evidence	\N	CYP2C9*65 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variant present in CYP2C9*65 is predicted to be deleterious in both SIFT and Polyphen predictions. There are no in vitro or clinical studies reported. Consensus was not achieved among experts and therefore uncertain function was assigned.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778199	306	CYP2D6	*140	\N	Unknown function	\N	n/a	778198	{}	No Evidence	\N	CYP2D6*140 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
779003	356	G6PD	Andalus	II/Deficient	II/Deficient	\N	\N	779002	{22293322,12497642,32425388,16088936,2393028}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.0, "East Asian": 0.00007233273, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
778815	356	G6PD	Minnesota, Marion, Gastonia, LeJeune	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778814	{22293322,1999409,1805484}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": 0.0, "European": 0.00001025599, "East Asian": 0.0, "Central/South Asian": 0.0, "African American/Afro-Caribbean": 0.0}	f
779087	162	NUDT15	*12	\N	Uncertain function	\N	\N	779086	{29519865,32094176}	Inadequate	\N	NUDT15*12 is assigned uncertain function based on inadequate evidence. An in vitro study expressed NUDT15*12 in HEK293 cells and found there was no effect on thiopurine sensitivity (32094176). An additional in vitro study found that NUDT15.12 exhibits decreased protein thermostability compared to NUDT15.1 (29519865). Patients carrying the NUDT15*12 allele had a 20% reduction in thiopurine dosing after the occurrence of adverse reactions (29519865). Seven out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*12-defining SNV (c.156C>G (p.F52L)) impairs protein function.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null}	f
3685423	195	RYR1	c.1475G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685422	{35849058}	\N	\N	PM1	{"Latino": null, "European": 0.0000246, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000801}	f
3685797	195	RYR1	c.11126C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685796	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777581	404	CYP2C19	*28	\N	Normal function	\N	\N	777580	{25001882,20712527}	Limited	\N	CYP2C19*28 is assigned normal function based on limited in vitro and computational evidence. An in vitro study found CYP2C19*28 had similar intrinsic clearance compared to wildtype with a mephenytoin substrate (25001882). A computational analysis including splice site, mFold and nonsynonymous mutation analysis, did not find a deleterious impact on enzyme function (20712527). Although CYP2C19*28 was found to have increased intrinsic clearance compared to wildtype with a clopidogrel substrate in vitro (25001882), the experts did not find this result convincing as computational analysis and in vitro data with mephenytoin did not support increased function. Therefore, consensus among experts was normal function based on limited evidence as it was determined the phenotypes containing this allele would be clinically similar to phenotypes comprising normal function alleles.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0037037036, "African American/Afro-Caribbean": null}	f
777793	386	CYP2C9	*63	Uncertain function	Uncertain function	\N	n/a	777792	{33536773}	Inadequate evidence	\N	CYP2C9*63 is assigned uncertain funciton due to inadequate evidence. The nonsynonymous variants present in CYP2C9*63 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": 0.0, "American": null, "European": 0.0, "Oceanian": null, "East Asian": null, "Near Eastern": 0.0, "Central/South Asian": 0.00050, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685461	195	RYR1	c.2654G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685460	{35849058}	\N	\N	None	{"Latino": 0.0000167, "European": 0.0002186, "East Asian": 0.0000669, "Near Eastern": null, "Central/South Asian": 0.0003184, "Sub-Saharan African": 0.0000533}	f
778055	400	CYP2D6	*61	\N	Uncertain function	\N	n/a	778054	{24647041,30366777}	Inadequate	\N	CYP2D6*61 is assigned uncertain function due to inadequate evidence. In vitro studies have found CYP2D6*61 demonstrated decreased to no detectable enzyme activity compared to wildtype with various substrates (24647041, 30366777) but consensus among experts was uncertain function.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3685493	195	RYR1	c.4400A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685492	{33767344}	\N	\N	BP4	{"Latino": null, "European": 0.000001744, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685525	195	RYR1	c.5890C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685524	{35849058}	\N	\N	BP4	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685533	195	RYR1	c.6304G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685532	{35849058}	\N	\N	PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685537	195	RYR1	c.6377G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685536	{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
779187	383	RYR1	c.6487C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779186	{33767344}	\N	\N	PS3_Mod, PS4_Mod, PM1_Sup, PM5, PP1_St, PP3_Mod, BS2_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685573	195	RYR1	c.6671G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685572	{33767344}	\N	\N	PM1	{"Latino": 0.000050, "European": 0.0000415, "East Asian": null, "Near Eastern": 0.000165, "Central/South Asian": 0.000022, "Sub-Saharan African": null}	f
3685599	195	RYR1	c.7035C>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685598	{35849058}	\N	\N	PS3_Mod, PS4_Mod, PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685601	195	RYR1	c.7036G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685600	{}	\N	Reference: MHS VCEP	PS4_Mod, PM1, PP3_Mod (Codes; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5d96e526-4b1b-4a3e-add6-6ceeae298c46)	{"Latino": 0.0000167, "European": 0.0000136, "East Asian": 0.0000223, "Near Eastern": null, "Central/South Asian": 0.000011, "Sub-Saharan African": 0.0000134}	f
3685617	195	RYR1	c.7075C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685616	{35849058}	\N	\N	PM1_Sup, PM5_Sup, PP3_Mod	{"Latino": 0.0000333, "European": 0.00000339, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000134}	f
3685633	195	RYR1	c.7123G>A	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685632	{33767344}	\N	\N	PS4_Sup, PM1_Sup, PM5, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779209	383	RYR1	c.7300G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779208	{33767344}	\N	\N	PS3, PS4, PM1, PP1_St, PP3_Mod, BS2	{"Latino": null, "European": 0.0001263, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000267}	f
779211	383	RYR1	c.7304G>A	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779210	{33767344}	\N	\N	PS3_Mod, PS4, PM1, PP1_St, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685657	195	RYR1	c.7310C>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685656	{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
8103011	9	RYR1	c.7625G>A	Variant of uncertain significance	Uncertain function	\N	n/a	8103010	{}	\N	Reference: MHS VCEP	PS3_Mod, PS4_Sup, BP4	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685713	195	RYR1	c.8054C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685712	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685721	195	RYR1	c.8290G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685720	{35849058}	\N	\N	None	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685733	195	RYR1	c.8638G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685732	{35849058}	\N	\N	PS4_Sup, PP3_Mod	{"Latino": null, "European": 0.000002542, "East Asian": null, "Near Eastern": 0.0001644, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685737	195	RYR1	c.8729C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685736	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685791	195	RYR1	c.10891G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685790	{35849058}	\N	\N	PS4_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685917	195	RYR1	c.14424C>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685916	{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
778051	400	CYP2D6	*59	\N	Decreased function	\N	0.5	778050	{17001296,26335396}	Moderate	\N	CYP2D6*59 is assigned decreased function based on moderate evidence. CYP2D6*59 has been described in subjects demonstrating decreased sparteine and dextromethorphan metabolism (17001296, 26335396). An in vitro study found CYP2D6*59 exhibited decreased mRNA levels and enzyme activity with a propafenone substrate compared to wildtype (17001296). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on moderate evidence.	{"Latino": null, "American": 0.001, "European": 0.003719603, "Oceanian": null, "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
778053	399	CYP2D6	*60	\N	No function	\N	0.0	778052	{19364831}	Limited	\N	CYP2D6*60 is assigned no function based on limited evidence. CYP2D6*60 is defined by an early stop codon suggesting a complete functional protein is not formed (19364831). 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": 0.0014483429, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
3318600	145	CYP4F2	*15	\N	\N	\N	\N	3318599	\N	\N	\N	\N	{"Latino": null, "American": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778837	356	G6PD	Aveiro	I/Deficient with CNSHA	I/Deficient with CNSHA	\N	\N	778836	{22293322,10666231}	limited	\N	Function assigned based on the WHO recommendations included in PMID 22293322.	{"Latino": null, "European": null, "East Asian": null, "Central/South Asian": null, "African American/Afro-Caribbean": null}	f
3685577	195	RYR1	c.6710G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685576	{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
3685587	195	RYR1	c.6847A>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685586	{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
779203	383	RYR1	c.7063C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779202	{33767344}	\N	\N	PS3_Mod, PS4, PM1, PP1_St, PP3_Mod	{"Latino": null, "European": 0.0000203, "East Asian": null, "Near Eastern": 0.0000338, "Central/South Asian": 0.000033, "Sub-Saharan African": null}	f
3685689	195	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
3685645	195	RYR1	c.7291G>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685644	{35849058}	\N	\N	PS3_Mod, PS4_Mod, PM1_Sup, PM5_Sup, PP1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685691	195	RYR1	c.7760A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685690	{35849058}	\N	\N	PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685719	195	RYR1	c.8198G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685718	{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
3685741	195	RYR1	c.9152G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685740	{35849058}	\N	\N	None	{"Latino": null, "European": 0.000024877778, "East Asian": null, "Near Eastern": 0.0041208, "Central/South Asian": 0.000011, "Sub-Saharan African": 0.0000134}	f
3685775	195	RYR1	c.10100A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685774	{}	\N	Reference: MHS VCEP	PS4_Sup (Codes, https://erepo.clinicalgenome.org/evrepo/ui/classification/824d3211-edc0-43c2-a2ac-734a25134ae6)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685831	195	RYR1	c.12064A>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685830	{35849058}	\N	\N	BP4	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685879	195	RYR1	c.13702C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685878	{33767344}	\N	\N	None	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685985	195	RYR1	c.14364+1G>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685984	{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
3685925	195	RYR1	c.14471T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685924	{35849058}	\N	\N	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
779235	383	RYR1	c.14477C>T	Pathogenic	Malignant Hyperthermia associated	\N	n/a	779234	{33767344}	\N	\N	PS3, PS4, PM1_Sup, PP1_St, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685971	195	RYR1	c.14818G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685970	{35849058}	\N	\N	PS4_Mod, PM1_Sup, PP3_Mod	{"Latino": null, "European": 0.000002542, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": 0.0000134}	f
778973	356	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
779245	383	RYR1	c.14693T>C	Variant of uncertain significance	Uncertain function	\N	n/a	779244	{}	\N	Reference: MHS VCEP	PM1_Sup, PP3_Mod, BS3_Sup (Codes; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e7eda2ef-a562-4e9c-816b-ec20dd82fe98)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685729	195	RYR1	c.8527T>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685728	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685739	195	RYR1	c.8926C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685738	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778809	356	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
777689	404	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
3685747	195	RYR1	c.9356G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685746	{35849058}	\N	\N	None	{"Latino": null, "European": 0.00000339, "East Asian": 0.0001782, "Near Eastern": null, "Central/South Asian": 0.000011, "Sub-Saharan African": 0.0000267}	f
3685799	195	RYR1	c.11132C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685798	{35849058}	\N	\N	PS4_Sup, PP1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685807	195	RYR1	c.11416G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685806	{35849058}	\N	\N	PS4_Sup, PP1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685853	195	RYR1	c.12532G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685852	{33767344}	\N	\N	PS4_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685859	195	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
777799	386	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
3685919	195	RYR1	c.14449A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685918	{35849058}	\N	\N	PS4_Sup, PM1_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685475	195	RYR1	c.3166G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685474	{35849058}	\N	\N	PS4_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685489	195	RYR1	c.4024A>G	Benign	Normal function	\N	n/a	3685488	{33767344}	\N	\N	BA1	{"Latino": 0.0117514, "European": 0.0004851, "East Asian": null, "Near Eastern": 0.0022508511, "Central/South Asian": 0.0004579, "Sub-Saharan African": 0.155337}	f
3685575	195	RYR1	c.6670C>T	Likely Benign	Normal function	\N	n/a	3685574	{35849058}	\N	\N	PM1, BS1	{"Latino": 0.0000167, "European": 0.0001271, "East Asian": null, "Near Eastern": 0.000165, "Central/South Asian": 0.0010759, "Sub-Saharan African": 0.000040}	f
3685597	195	RYR1	c.7032G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685596	{35849058}	\N	\N	PM1	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685677	195	RYR1	c.7373G>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685676	{35849058}	\N	\N	PS4_Mod, PM1_Sup, PM5, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778019	400	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	306	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
3685945	195	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
2091245	304	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	356	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	356	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	356	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
3685813	195	RYR1	c.11723A>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685812	{35849058}	\N	\N	PS4_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685835	195	RYR1	c.12121C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685834	{35849058}	\N	\N	BP4	{"Latino": null, "European": 0.0000178, "East Asian": 0.0000446, "Near Eastern": null, "Central/South Asian": 0.000011, "Sub-Saharan African": null}	f
3685857	195	RYR1	c.12553G>A	Likely Benign	Normal function	\N	n/a	3685856	{}	\N	Reference: Based on MHS VECP submission to ClinVar date 20-Apr-26	BS2_Moderate, BP4	{"Latino": 0.0003499, "European": 0.00080027385, "East Asian": null, "Near Eastern": 0.000165, "Central/South Asian": null, "Sub-Saharan African": 0.0001199}	f
3685867	195	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
3685845	195	RYR1	c.12383C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685844	{35849058}	\N	\N	PS4_Sup, BP4	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
778071	400	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
3318602	145	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	356	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
3685631	195	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
3685861	195	RYR1	c.12700G>C	Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685860	{}	\N	Reference: MHS VCEP	PP1_Strong, PP3_Moderate, PS4 (Uuid: dceccd7a-e299-418d-ba71-5d141dd81508)	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
779207	383	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
3685863	195	RYR1	c.12700G>T	Likely Pathogenic	Malignant Hyperthermia associated	\N	n/a	3685862	{35849058}	\N	\N	PS1_Mod, PS4_Mod, PP1, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685643	195	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
3685841	195	RYR1	c.12310G>C	Likely Benign	Normal function	\N	n/a	3685840	{35849058}	\N	\N	BS2_Mod, BP4	{"Latino": null, "European": 0.00000339, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685873	195	RYR1	c.13513G>C	Benign	Normal function	\N	n/a	3685872	{33767344}	\N	\N	BA1	{"Latino": 0.001594, "European": 0.0062500355, "East Asian": null, "Near Eastern": 0.0040265135, "Central/South Asian": 0.002637, "Sub-Saharan African": 0.0010849}	f
3685893	195	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
3685897	195	RYR1	c.14126C>T	Variant of uncertain significance	Uncertain function	\N	n/a	3685896	{33767344}	\N	\N	PM1_Sup, PP3_Mod, BS3_Sup	{"Latino": 0.0000167, "European": 0.000004238, "East Asian": 0.0000223, "Near Eastern": 0.0009805, "Central/South Asian": 0.000033, "Sub-Saharan African": 0.0000133}	f
3685901	195	RYR1	c.14186A>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685900	{35849058}	\N	\N	PM1_Sup	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
3685915	195	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
3685921	195	RYR1	c.14458G>A	Variant of uncertain significance	Uncertain function	\N	n/a	3685920	{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
3685933	195	RYR1	c.14509C>G	Variant of uncertain significance	Uncertain function	\N	n/a	3685932	{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	195	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
3685977	195	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
3685983	195	RYR1	c.15060G>C	Variant of uncertain significance	Uncertain function	\N	n/a	3685982	{35849058}	\N	\N	PS4_Sup, PP3_Mod	{"Latino": null, "European": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null}	f
777805	386	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
779324	382	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
779340	382	SLCO1B1	*32	\N	Uncertain function	\N	\N	779339	{22147369}	Inadequate	\N	SLCO1B1*32 is assigned uncertain function based on no in vitro evidence and limited clinical data. One clinical study showed no statistical difference in methotrexate clearance for one heterozygous patient (22147369). Therefore, consensus among experts was uncertain function due to inadequate evidence.	{"American": null, "European": null, "Oceanian": null, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778791	356	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	356	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	195	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	195	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
1002624	376	SLCO1B1	*1	\N	Normal function	\N	\N	1002623	{10601278,10644574,10358072,12811365,15116054,15226675,21245207,32961594}	Definitive	\N	SLCO1B1*1 is the reference allele, associated with normal OATP1B1 activity based on a large number of in vitro (10601278, 10644574, 10358072) and clinical data (12811365, 15116054, 15226675, 21245207, 32961594).	{"American": 0.37, "European": 0.4027496, "Oceanian": 0.33999997, "East Asian": 0.25522262, "Near Eastern": 0.49, "Central/South Asian": 0.46972018, "Sub-Saharan African": 0.17130345, "African American/Afro-Caribbean": 0.23000002}	t
3685931	195	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	383	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	195	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
779292	382	SLCO1B1	*8	\N	Uncertain function	\N	\N	779291	{11477075,12490595}	Inadequate	\N	SLCO1B1*8 is assigned uncertain function based on in vitro studies demonstrating unaltered 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": 0.0, "Oceanian": null, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
779298	382	SLCO1B1	*11	\N	Uncertain function	\N	\N	779297	{11477075,12490595}	Inadequate	\N	SLCO1B1*11 is assigned uncertain function based on in vitro studies demonstrating reduced uptake of rifampin (12490595), but not of estrone sulfate or estradiol 17beta-d-glucuronide (11477075) and 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
778817	356	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
1002690	376	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
1002696	376	SLCO1B1	*42	\N	Uncertain function	\N	\N	1002695	{33658230}	Inadequate	\N	SLCO1B1*42 is assigned uncertain function based on limited in vitro evidence. It contains two variants, rs2306283 and rs141467543. One in vitro study found normal protein expression and transport for the rs141467543 variant (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
1002706	376	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
777789	404	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
777591	404	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
778921	356	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
779338	383	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
777775	404	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
1002694	376	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
779699	330	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	400	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	356	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	356	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	162	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	195	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
779441	382	TPMT	*23	\N	No function	\N	\N	779440	{17885628,18708949,23025308,31005613}	Limited	\N	TPMT*23 is assigned no function based on limited evidence. Erythrocytes from individuals genotyped TPMT*3A/*23 or *3C/*23 exhibited low activity (17885628). An in vitro study using a mammalian cell expression system found that TPMT.23 exhibited decreased affinity for 6-TG and TPMT.23 enzymatic activity is decreased by 40% compared to TPMT.1 (18708949). Published in silico modeling suggests that TPMT.23 exhibited decreased protein stability as well as altered substrate and co-factor binding (17885628, 23025308). Similarly, seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*23-defining SNV, c.500C>G (p.A167G), impairs protein function.	{"Latino": 0.0, "European": 0.000026239319, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777993	400	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
778783	356	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
779421	382	TPMT	*13	\N	No function	\N	\N	779420	{16220112,18708949,13679074}	Limited	\N	TPMT*13 is assigned no function based on limited evidence. TPMT*13 was identified in an individual who experienced severe leucopenia after standard azathioprine dosing. In vitro studies found that TPMT.13 protein expression is decreased, enzymatic activity is decreased by 40-80%, and TPMT.13 exhibited decreased affinity for 6-MP, 6-TG, and SAM relative to TPMT.1 in mammalian (16220112, 18708949) and yeast cells (13679074). Six out of ten variant effect predictors tested by CPIC staff predict that the TPMT*13-defining SNV, c.83A>T (p.E28V), 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
777483	404	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
779429	382	TPMT	*17	\N	No function	\N	\N	779428	{18708949,15226673}	Limited	\N	TPMT*17 is assigned no function based on limited evidence. Erythrocytes from an individual genotyped TPMT*1/*17 exhibited intermediate activity (15226673). An in vitro study using a mammalian cell expression system found that TPMT.17 exhibited decreased affinity for 6-TG and enzymatic activity is decreased by 90% compared to TPMT.1 (18708949). Three out of ten variant effect predictors tested by CPIC staff predict that the TPMT*17-defining SNV, c.124C>G (p.Q42E), impairs protein function.	{"Latino": null, "European": 0.00040, "East Asian": null, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777783	404	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
779467	382	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
3685619	195	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	195	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
779399	382	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
777787	404	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	386	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
778941	356	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
779413	382	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
778043	400	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	400	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	399	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	356	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	356	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
779453	382	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
779471	382	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
778115	400	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	356	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	356	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
3685429	195	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
3685435	195	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
3685965	195	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
3685541	195	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
2784573	174	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	174	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
3685555	195	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
779427	382	TPMT	*16	\N	No function	\N	\N	779426	{18708949,15652243,15226673,33118454,32973300}	Moderate	\N	TPMT*16 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*1/*16 exhibited intermediate enzymatic activity (15226673, 15652243, 33118454). In vitro studies found that TPMT.16 exhibited decreased affinity for 6-TG and enzymatic activity was decreased by 84% and 68% relative to TPMT.1 in mammalian (18708949) and yeast (15652243) cells, respectively. An in silico prediction model of TPMT variant functionality can predict >95% of variance when including TPMT*16 along with the most common variants TPMT*2, *3A, and *3C, compared to 70% without TPMT*16 (32973300). Five out of ten variant effect predictors tested by CPIC staff predict that the TPMT*16-defining SNV, c.488G>A (p.R163H), impairs protein function.	{"Latino": 0.00005819, "European": 0.0010142878, "East Asian": 0.00020803267, "Near Eastern": null, "Central/South Asian": 0.0005212, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
779431	382	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
779433	382	TPMT	*19	\N	Uncertain function	\N	\N	779432	{15652243,18708949}	Inadequate	\N	TPMT*19 is assigned uncertain function based on inadequate evidence. Erythrocytes from an individual genotyped TPMT*1/*19 exhibited normal activity (15652243). In an in vitro study using a yeast expression system, TPMT.19 activity was decreased by 30% relative to TPMT.1 using 6-TG as a substrate (15652243). Another in vitro study using a mammalian expression system found TPMT.19 enzymatic activity was decreased by 40% compared to TPMT.1 (18708949). Six out of ten variant effect predictors tested by CPIC staff predict that the TPMT*19-defining SNV, c.365A>C (p.K122T), 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
3685679	195	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
779075	384	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
777709	404	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
779083	162	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	162	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	195	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
777727	404	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
779401	382	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
779403	382	TPMT	*4	\N	No function	\N	\N	779402	{9246020,9486974,12880540}	Strong	\N	TPMT*4 is assigned no function based on strong evidence. The SNV characteristic of TPMT*4 (c.626-1G>A) is located in the splice junction between intron 9 and exon 10 and disrupts the canonical splice site, resulting in production of a truncated protein. Erythrocytes from individuals heterozygous for TPMT*4 exhibited intermediate TPMT enzymatic activity (9486974, 12880540), while erythrocytes from individuals carrying TPMT*4 in combination with another no function allele had very low TPMT enzymatic activity (9246020, 9486974). The in silico variant effect predictors, CADD and PhD-SNPg, predict that the TPMT*4-deifning SNV, c. 626-1G>A, impairs protein function. Additionally, c.626-1G>A is predicted to result in the loss of the acceptor splice site by SpliceAI.	{"Latino": 0.0, "European": 0.000058889815, "East Asian": 0.0, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
778223	397	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	396	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
779508	212	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
778231	397	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	396	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	397	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	383	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	195	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
779407	382	TPMT	*6	\N	No function	\N	\N	779406	{9246020,16220112,18708949,30023734,39696474}	Moderate	\N	TPMT*6 is assigned no function based on moderate evidence. Erythrocytes from an individual genotyped TPMT*1/*6 exhibited intermediate enzymatic activity toward 6-MP (9246020). An individual carrying TPMT*6 experienced severe leukopenia following standard azathioprine dosing (39696474). In vitro studies using mammalian cell expression systems demonstrate that TPMT.6 protein expression is substantially decreased compared to TPMT.1 (16220112). Additionally, TPMT.6 exhibited reduced substrate affinity for 6-TG, reduced clearance of 6-TG and 6-MP, and enzymatic activity was decreased by 60-80% in vitro (16220112, 18708949). Recombinant TPMT.6 expressed and purified from bacterial cells exhibited decreased protein stability, however activity was unaffected when using 6-MP as a substrate (30023734). Despite conflicting in vitro evidence, the experts agreed to assign no function based on the available clinical data. Five out of ten variant effect predictors tested by CPIC staff predict that the TPMT*6-defining SNV, c.539A>T (p.Y180F), impairs protein function.	{"Latino": 0.00002916, "European": 0.0, "East Asian": 0.0022042317, "Near Eastern": null, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
779510	212	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
777739	404	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
779069	384	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	195	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
777441	404	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	404	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	404	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
779465	382	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
778123	399	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
777669	403	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
3685469	195	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	195	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	195	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
777439	404	CYP2B6	*9	Decreased function	Decreased function	\N	\N	777438	{11243870,14551287,15622315,18171905,21659470,22927450,23080225,24260284,30085944,30201214,3090656,32238417,35538637,30906561}	Strong	\N	CYP2B6*9 (c.516G>T, p.Q172H/splice defect) - Decreased function: CYP2B6*9 is assigned decreased function. When c.516G>T occurs alone, it defines CYP2B6*9. The c.516G>T variant causes aberrant splicing (14551287, 18171905, 24260284) and is in high linkage disequilibrium with c.785A>G, which is part of the CYP2B6*6 haplotype. c.516G>T is also present in several other haplotypes (e.g., CYP2B6*7, *13, *19, *20, *26, *34, *36, *37 and *38). These haplotypes make it difficult to ascertain the presence of *9 and its clinical function. Although several studies have reported a significant association between c.516G>T and efavirenz exposure (over 3-fold increase) in patient plasma and/or hair samples (15622315, 22927450, 23080225), these associations were erroneously attributed to CYP2B6*9 rather than *6. Several in vitro studies using cDNA expression systems show that CYP2B6*9 decreases activity towards efavirenz, bupropion, methadone, ketamine, and nicotine (21659470, 30085944, 30906561, 32238417, 35538637), while others have shown no or increased activity (11243870, 30201214). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. At present, functional information is informed by the fact that alleles with c.516G>T (e.g., CYP2B6*6) have been associated with decreased function (see description for CYP2B6*6 allele). Therefore, consensus among experts was decreased function based on strong evidence.	{"Latino": 0.07266471, "European": 0.0147, "Oceanian": 0.01, "East Asian": 0.034411334, "Near Eastern": 0.102, "Central/South Asian": 0.059, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.046484537}	f
777681	404	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
779455	382	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
1103382	306	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	304	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	304	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	397	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
777487	404	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
777491	404	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
2899151	193	CYP2B6	*43	Decreased function	Decreased function	\N	\N	2899150	{14551287,18171905,24260284,38596098}	Limited	\N	CYP2B6*43 (c.516G>T, p.Q172H/splice defect; c.785A>G, p.K262R; c.1390G>A, p.A464T) – Decreased function: CYP2B6*43 is assigned decreased function. CYP2B6*43 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.A464T 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
3827897	177	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	162	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	162	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
778797	356	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
3685953	195	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
777265	404	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	404	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
777563	404	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
777677	404	CYP2C9	*5	Decreased function	Decreased function	\N	0.5	777676	{23752738,15289788,11455026,16220110,17504998,21811894,11901091}	Strong	\N	CYP2C9*5 is assigned decreased function based on strong evidence in heterozygous patients and in vitro studies. Three subjects carrying the CYP2C9*5 allele (CYP2C9*1/*5, CYP2C9*5/*6, CYP2C9*5/*8 genotype) had decreased losartan metabolism compared to wildtype based on urinary metabolites after a single 25mg dose (15289788). Two CYP2C9 *1/*5 subjects, one CYP2C9 *5/*6 subject, and one CYP2C9*5/*8 subject had lower phenytoin metabolism compared to wildtype based on urinary excretion of a phenytoin metabolite after a single 300mg dose. Additionally, the CYP2C9 *5/*6 subject demonstrated the lowest phenytoin metabolism as the only subject of the 109 subject cohort to have a urinary metabolite concentration below the limit of quantification (16220110). One CYP2C9 *5/*8 demonstrated the lowest acenocoumarol metabolism based on plasma concentrations in a 36 subject cohort (21811894). One CYP2C9*1/*5 subject demonstrated decreased indisulam metabolism with an AUC nearly two times greater than wildtype subjects (17504998). These results correlated with in vitro pharmacokinetic studies which demonstrated decreased clearance of warfarin, diclofenac, flurbiprofen, naproxen, and piroxicam compared to wildtype (11455026, 11901091). A separate in vitro study found CYP2C9*5 has decreased enzyme activity compared to wildtype with warfarin and tolbutamide substrates that (23752738). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on strong evidence.	{"Latino": 0.00871987, "American": 0.0014913112, "European": 0.00017448276, "Oceanian": null, "East Asian": 0.0, "Near Eastern": 0.00052266667, "Central/South Asian": 0.0, "Sub-Saharan African": 0.010325842, "African American/Afro-Caribbean": 0.011626912}	f
777693	404	CYP2C9	*13	Decreased function	No function	\N	0.0	777692	{23752738,16308280,15764711,25951663,19541829,16740353,20814155,19604036,21395648,21726410,21842338,22735459,23844998,24118918,24464553,25142737,25476996,25614704,25832633,25884291,27163851,25144335,27377818,27864660,15606435,24077631}	Definitive	\N	CYP2C9*13 is assigned no function based on definitive evidence in heterozygous patients. Subjects with CYP2C9*1/*13 genotype repeatedly demonstrated decreased clearance and increased AUC compared to wildtype subjects and similar clearance and AUC compared to CYP2C9*1/*3 subjects in multiple studies with different substrates (19604036, 21395648, 21726410, 21842338, 22735459, 27377818, 27864660, 15606435). Two studies correlated in vitro data with clinical data and also found increased AUC and decreased clearance compared to wildtype with lornoxicam and tolbutamide (15764711, 25614704). Additionally, a CYP2C9*3/*13 subject had a greater decrease in tolbutamide clearance compared to the CYP2C9*1/*13 subject (25614704). This was also demonstrated in another CYP2C9*3/*13 subject with decreased lornoxicam clearance and increased AUC compared to wildtype, CYP2C9 *1/*3, and CYP2C9*1/*2 subjects (15606435). Multiple in vitro studies demonstrate CYP2C9*13 exhibits decreased metabolism comparable to that observed for CYP2C9*3 for numerous substrates (23844998, 24118918, 24464553, 25142737, 25476996, 25832633, 25884291, 27163851, 24077631, 25951663, 19541829, 20814155, 23752738, 16308280, 25144335) and one model suggests the decreased metabolism across substrates is due to a side chain rotation which blocks the catalytic site (16740353). Therefore, consensus among experts was no function with an activity value of 0 based on definitive evidence.	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0033167014, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
777717	404	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
777735	404	CYP2C9	*34	Uncertain function	Uncertain function	\N	n/a	777734	{23752738,18971529,19541829,23844998,24118918,25142737,25144335,25951663,25476996,25614704,25832633,25884291,25924705,27163851,24077631}	Inadequate evidence	\N	CYP2C9*34 is assigned uncertain function due to inadequate evidence. Although one subject with CYP2C9*1/*34 genotype exhibited decreased clearance compared to wildtype subjects based on tolbutamide plasma concentrations after one 500mg dose (25614704), in vitro studies found CYP2C9*34 demonstrated enzyme activity ranging from decreased to increased compared to wildtype with various substrates (23752738, 18971529, 23844998, 19541829, 24118918, 25142737, 25476996, 25614704, 25832633, 25884291, 25924705, 27163851, 24077631, 25144335, 25951663). Consensus was not achieved among experts and therefore uncertain function was assigned..	{"Latino": null, "American": null, "European": null, "Oceanian": null, "East Asian": 0.0002119417, "Near Eastern": null, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777741	404	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
777469	403	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
777593	404	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
777755	404	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
777777	404	CYP2C9	*55	Decreased function	Decreased function	\N	0.5	777776	{24077631,24118918,25142737,25144335,25476996,25832633,25884291,25951663,25924705,27163851,23844998}	Limited	\N	CYP2C9*55 is assigned decreased function based on limited evidence. Multiple in vitro studies found CYP2C9*55 demonstrated decreased clearance compared to wildtype (24077631, 24118918, 25144335, 25476996, 25832633, 25951663, 25924705, 27163851, 23844998). Although two in vitro studies showed CYP2C9*55 had similar or increased 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 or similar 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 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": 0.0104, "Near Eastern": 0.0, "Central/South Asian": 0.0, "Sub-Saharan African": null, "African American/Afro-Caribbean": null}	f
777537	404	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
777707	404	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
778831	356	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	356	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	356	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	356	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	356	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	356	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
777671	404	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
8101127	4	CYP3A5	*10	\N	\N	\N	\N	8101126	\N	\N	\N	\N	\N	f
8101129	4	CYP3A5	*11	\N	\N	\N	\N	8101128	\N	\N	\N	\N	\N	f
778189	399	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
8101106	4	CYP2D6	*186	\N	\N	\N	\N	8101105	\N	\N	\N	\N	\N	f
3827885	177	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	49	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	177	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	177	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	177	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
779071	384	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
779280	383	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
8102297	4	NUDT15	*22	\N	\N	\N	\N	8102296	\N	\N	\N	\N	\N	f
8102299	4	NUDT15	*23	\N	\N	\N	\N	8102298	\N	\N	\N	\N	\N	f
779294	383	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
2899163	193	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
779419	382	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	404	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	404	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	404	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	403	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
777437	404	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	404	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	404	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
2091253	304	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
777459	404	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
777481	404	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
777489	404	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
777431	404	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
777457	404	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
2899153	193	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
777583	404	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
777549	404	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	404	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	404	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
777745	404	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
777535	404	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
777703	404	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
777781	404	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
777965	400	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
777679	404	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
778129	399	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
777695	404	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
777747	404	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
778151	399	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	304	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
777683	404	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	386	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
777725	404	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
778027	400	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
5294111	96	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
778127	399	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
778155	399	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	400	CYP2D6	*18	\N	No function	\N	0.0	777968	{8946471,10471060,18784265,24647041,30366777}	Moderate	\N	CYP2D6*18 is assigned no function based on moderate evidence. CYP2D6*18 is defined by a 9 base insertion yielding a nonfunctional enzyme and has been described in subjects demonstrating markedly decreased metabolism of sparteine and debrisoquine (8946471, 10471060). Multiple in vitro studies found CYP2D6*18 had decreased enzyme activity compared to wildtype with various substrates (8946471, 18784265, 24647041, 30366777). Therefore, consensus among experts was no function with an activity value of 0 based on moderate evidence.	{"Latino": null, "American": null, "European": 0.0, "Oceanian": null, "East Asian": 0.0013486103, "Near Eastern": 0.0, "Central/South Asian": null, "Sub-Saharan African": null, "African American/Afro-Caribbean": 0.0}	f
778007	400	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
1777311	304	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
777947	400	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	400	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
1609528	306	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
778456	385	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	385	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
3827873	177	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	177	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
6481219	42	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
6481217	42	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
7219573	26	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
6481227	42	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
6481275	42	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
6481283	42	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
779079	384	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
7219575	26	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
779425	382	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
6481197	42	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
3685349	195	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
3685753	195	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
6481215	42	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
7096549	28	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
779306	382	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
779459	382	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
779463	382	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
779437	382	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
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