Submissions for variant NM_001035.3(RYR2):c.7808C>T (p.Ala2603Val)

dbSNP: rs752607318

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223605	SCV000272396	uncertain significance	not specified	2016-01-11	criteria provided, single submitter	clinical testing	The p.Ala2603Val variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/22080 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s752607318). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Ala2603Val variant is uncertain.
GeneDx	RCV000767031	SCV000565771	uncertain significance	not provided	2017-03-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. The A2603V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the A2603V 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 not conserved across species and where valine is the wild type in several species. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the A2603V variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).
Invitae	RCV002518198	SCV000957277	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2603 of the RYR2 protein (p.Ala2603Val). This variant is present in population databases (rs752607318, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 229223). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001187345	SCV001354116	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 4/197016 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.
Ambry Genetics	RCV002408933	SCV002673316	uncertain significance	Cardiovascular phenotype	2020-12-31	criteria provided, single submitter	clinical testing	The p.A2603V variant (also known as c.7808C>T), located in coding exon 51 of the RYR2 gene, results from a C to T substitution at nucleotide position 7808. The alanine at codon 2603 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003997753	SCV004822696	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-01-11	criteria provided, single submitter	clinical testing	This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 4/197016 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.