Submissions for variant NM_001035.3(RYR2):c.7689A>G (p.Lys2563=)

gnomAD frequency: 0.00009  dbSNP: rs201082550

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001720137	SCV000522182	likely benign	not provided	2020-12-09	criteria provided, single submitter	clinical testing
Invitae	RCV002521607	SCV000554584	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777812	SCV000913807	likely benign	Cardiomyopathy	2018-05-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797718	SCV002041604	benign	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.7689A>G alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a cryptic 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 249284 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.7689A>G in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (MYH7 c.2717A>G, p.D906G), providing supporting evidence for a benign role. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002402144	SCV002674233	likely benign	Cardiovascular phenotype	2018-03-21	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.
PreventionGenetics, part of Exact Sciences	RCV003972613	SCV004789446	likely benign	RYR2-related condition	2019-04-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).