ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2848G>T (p.Val950Leu) (rs794728731)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182704 SCV000235084 uncertain significance not provided 2014-04-14 criteria provided, single submitter clinical testing p.Val950Leu (GTG>TTG): c.2848 G>T in exon 25 of the RYR2 gene (NM_001035.2). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The V950L variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The V950L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis predicts this variant likely does not alter the protein structure/function. Missense mutations in nearby residues have not been reported in association with RYR2-related phenotype, and the V950L variant does not occur in any of the RYR2 mutation hot spots" (Medeiros-Domingo A et al., 2009). However, this substitution occurs at a position that is conserved across species. Furthermore, the V950L variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s)."
Invitae RCV000552549 SCV000637543 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 950 of the RYR2 protein (p.Val950Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201233). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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