ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.7808C>T (p.Ala2603Val) (rs752607318)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 RCV000816754 SCV000957277 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2603 of the RYR2 protein (p.Ala2603Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs752607318, ExAC 0.005%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 229223). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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