ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13666G>C (p.Ala4556Pro) (rs189345192)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182839 SCV000235227 uncertain significance not provided 2014-05-14 criteria provided, single submitter clinical testing p.Ala4556Pro (GCA>CCA): c.13666 G>C in exon 94 of the RYR2 gene (NM_001035.2). Although the A4556P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge, a sequence change affecting this same residue, A4556T, has been reported in one individual referred for LQTS testing and was absent from 400 reference alleles; however, no specific clinical information was provided on this individual, and no segregation analysis or functional studies were available to support pathogenicity (Tester DJ et al., 2005). The A4556P variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense mutations in nearby residues (H4558Y, S4565R) have been reported in association with RYR2-related phenotype, supporting the functional importance of this region of the protein. However, the A4556P variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is moderately conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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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