Submissions for variant NM_001035.3(RYR2):c.6958G>A (p.Val2320Met)

dbSNP: rs1057522884

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443473	SCV000529839	uncertain significance	not provided	2016-07-07	criteria provided, single submitter	clinical testing	The V2320M variant in the RYR2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V2320M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V2320M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (A2317E and V2321M) have been reported in the Human Gene Mutation Database in association with RYR2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V2320M as a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001188682	SCV001355808	uncertain significance	Cardiomyopathy	2021-02-19	criteria provided, single submitter	clinical testing	This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/249138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV002526332	SCV001511500	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-06-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 387716). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2320 of the RYR2 protein (p.Val2320Met).
Baylor Genetics	RCV001337099	SCV001530676	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-07-16	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
PreventionGenetics, part of Exact Sciences	RCV003401427	SCV004104751	uncertain significance	RYR2-related condition	2023-02-15	criteria provided, single submitter	clinical testing	The RYR2 c.6958G>A variant is predicted to result in the amino acid substitution p.Val2320Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-237802344-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.