ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5717T>C (p.Met1906Thr) (rs748307254)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182734 SCV000235118 uncertain significance not provided 2012-07-10 criteria provided, single submitter clinical testing p.Met1906Thr (ATG>ACG): c.5717 T>C in exon 38 of the RYR2 gene (NM_001035.2). The Met1906Thr variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Met1906Thr results in a non-conservative amino acid substitution of a non-polar Methionine residue with a polar Threonine residue at a position that is conserved across species. In silico analysis predicts Met1906Thr is probably damaging to the protein structure/function. Also, the NHLBI ESP Exome Variant Server reports Met1906Thr 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. Nevertheless, no mutations in nearby codons have been reported in association with ARVC or an RYR2-related phenotype, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Met1906Thr is a disease-causing 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 RCV000686090 SCV000813593 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1906 of the RYR2 protein (p.Met1906Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs748307254, ExAC 0.06%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201257). 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.
Color RCV001189920 SCV001357305 uncertain significance Cardiomyopathy 2019-01-15 criteria provided, single submitter clinical testing

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