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

Total submissions: 7

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	RCV000766718	SCV000541655	likely benign	not provided	2019-02-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620555	SCV000735828	likely benign	Cardiovascular phenotype	2018-04-10	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: 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	RCV000769789	SCV000904500	uncertain significance	Cardiomyopathy	2018-09-24	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015), an individual affected with sudden unexplained death (PMID: 22677073) and an individual affected with dilated cardiomyopathy (PMID: 24503780). This variant has also been observed in individuals without a known history of cardiovascular disorders (PMID: 23861362, 27153395). This variant is fairly common in the general population and has been identified in 110/277002 chromosomes (100/126578 non-Finnish European chromosomes, 0.08%) by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.