Submissions for variant NM_001035.3(RYR2):c.6337G>A (p.Val2113Met) (rs186906598)

Total submissions: 9

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 type 1	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Partners HealthCare 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	uncertain significance	not provided	2018-10-24	criteria provided, single submitter	clinical testing	The V2113M variant of uncertain significance in the RYR2 gene has been reported in a 36-year-old patient with sudden unexplained death after exertion and in a 50-year-old Caucasian female with a clinical diagnosis of dilated cardiomyopathy (DCM) with premature ventricular contractions (PVCs), tachycardia, and a family history of DCM and sudden cardiac death (Tester et al., 2012; Pugh et al., 2014). While this variant has also been identified in several individuals referred for cardiology testing at GeneDx, segregation data are either absent or limited, and some of these individuals harbored an additional cardiogenetic variant. In addition, V2113M has been observed in 100/126,578 alleles (0.08%) from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). V2113M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Lastly, the V2113M variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variant occur (Medeiros- Domingo et al., 2009).
Invitae	RCV001084786	SCV000541655	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2020-11-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620555	SCV000735828	likely benign	Cardiovascular phenotype	2018-04-10	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Subpopulation frequency in support of benign classification
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 Health, Inc	RCV000769789	SCV000904500	likely benign	Cardiomyopathy	2020-04-15	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000171764	SCV001255546	likely benign	Catecholaminergic polymorphic ventricular tachycardia type 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 Clinical Services Laboratory,Illumina	RCV001099125	SCV001255547	uncertain significance	Arrhythmogenic right ventricular dysplasia, familial, 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.