Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182700 | SCV000235079 | uncertain significance | not provided | 2014-05-20 | criteria provided, single submitter | clinical testing | p.His836Arg (CAC>CGC): c.2507 A>G in exon 22 of the RYR2 gene (NM_001035.2). The H836R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H836R 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. The H836R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no mutations affecting nearby residues have been reported in the RYR2 gene in association with CPVT, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. 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 CARDIOMYOPATHY panel(s). |