Submissions for variant NM_001035.3(RYR2):c.10381A>G (p.Met3461Val)

gnomAD frequency: 0.00038  dbSNP: rs147512481

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171766	SCV000055288	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Invitae	RCV002515253	SCV000637473	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620370	SCV000734909	likely benign	Cardiovascular phenotype	2020-01-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000171766	SCV000970916	likely benign	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180037	SCV001344885	likely benign	Cardiomyopathy	2018-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194069	SCV001363325	benign	not specified	2019-10-15	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.10381A>G (p.Met3461Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248876 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 72 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.10381A>G has been reported in the literature in individuals with limited information (Ng_2013, Landstrom_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Three ClinVar submissions (evaluation after 2014) cite the variant twice as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.