ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.818C>T (p.Ser273Phe) (rs794728715)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182668 SCV000235047 likely pathogenic not provided 2012-08-02 criteria provided, single submitter clinical testing p.Ser273Phe (TCC>TTC): c.818 C>T in exon 11 of the RYR2 gene (NM_001035.2). The Ser273Phe variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser273Phe results in a non-conservative amino acid substitution of polar Serine residue with a non-polar Phenylalanine residue at a position that is conserved across species. In silico analysis predicts Ser273Phe is probably damaging to the protein structure/function. Ser273Phe occurs in the N-terminal mutation hotspot' of the RYR2 gene (Medeiros-Domingo A et al., 2009). Furthermore, the NHLBI ESP Exome Variant Server reports Ser273Phe was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Ser273Phe is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this 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 RCV000694005 SCV000822429 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 273 of the RYR2 protein (p.Ser273Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201203). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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