ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1675A>G (p.Ile559Val) (rs773609522)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182687 SCV000235066 uncertain significance not provided 2014-07-01 criteria provided, single submitter clinical testing p.Ile559Val (ATC>GTC): c.1675 A>G in exon 17 of the RYR2 gene (NM_001035.2). Approximately 50% of patients with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) are rare (McNally et al., 2009; Napolitano C et al., 2012). The I559V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I559V 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 addition, this substitution occurs at a position that is relatively well conserved across species (V559 accepted in a few species). Furthermore, a missense mutation in a nearby residue (A549V) has been reported in association with CPVT, supporting the functional importance of this region of the protein. Nevertheless, the I559V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, in silico analysis predicts this variant likely does not alter the protein structure/function. 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).

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