ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4010A>G (p.Tyr1337Cys) (rs765369749)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics,University of Leuven RCV000768529 SCV000886848 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000182718 SCV000235100 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing p.Tyr1337Cys (TAT>TGT): c.4010 A>G in exon 31 of the RYR2 gene (NM_001035.2). The Y1337C variant has not been published as a disease-causing mutation or as a benign polymorphism to our knowledge. The Y1337C 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. The Y1337C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not well conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with ARVC, suggesting this region of the protein may be tolerant to change. Furthermore, this variant is not located in one of the mutation hot spot regions in the RYR2 gene (Medeiros-Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is primarily an autosomal dominant disease characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death (McNally E et al., 2009; Nava A et al., 2000). ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to-cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 2009). 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 variant is found in ARVC panel(s).
Invitae RCV000639078 SCV000760639 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-12-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1337 of the RYR2 protein (p.Tyr1337Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs765369749, ExAC 0.003%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201243). 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 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.

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