Submissions for variant NM_001035.3(RYR2):c.6337G>A (p.Val2113Met)

gnomAD frequency: 0.00045  dbSNP: rs186906598

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171764	SCV000050779	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036777	SCV000060432	uncertain significance	not specified	2014-06-05	criteria provided, single submitter	clinical testing	The Val2113Met variant in RYR2 has been reported in 1 Caucasian adult with sudde n unexplained death and in 1 Caucasian adult with DCM (Tester 2012, Pugh 2014). This variant has also been identified in 6/8320 European American chromosomes b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s186906598). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the Val2113Met variant is uncertain.
GeneDx	RCV000766718	SCV000235125	likely benign	not provided	2023-09-14	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000171764	SCV000541655	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620555	SCV000735828	likely benign	Cardiovascular phenotype	2018-04-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769789	SCV000901214	uncertain significance	Cardiomyopathy	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769789	SCV000904500	likely benign	Cardiomyopathy	2020-04-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000171764	SCV001255546	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2017-09-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001099125	SCV001255547	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2017-09-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
All of Us Research Program, National Institutes of Health	RCV004803128	SCV005426795	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036777	SCV005726649	likely benign	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.6337G>A (p.Val2113Met) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 249094 control chromosomes, predominantly at a frequency of 0.00074 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 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05). To our knowledge, no experimental evidence demonstrating the variant's impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 43813). Based on the evidence outlined above, the variant was classified as likely benign.