ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.218T>G (p.Leu73Arg) (rs794728705)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182652 SCV000235030 likely pathogenic not provided 2013-08-06 criteria provided, single submitter clinical testing p.Leu73Arg (CTC>CGC): c.218 T>G in exon 3 of the RYR2 gene (NM_001035.2). The Leu73Arg variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Leu73Arg results in a non-conservative amino acid substitution of a non-polar Leucine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Leu73Arg is damaging to the protein structure/function. A mutation in a nearby residue (Ala77Val) has been reported in association with ARVC, further supporting the functional importance of this region of the protein. The Leu73Arg 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. In summary, while Leu73Arg 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).

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