ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.364C>T (p.Arg122Cys) (rs397516527)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766703 SCV000235033 uncertain significance not provided 2014-08-20 criteria provided, single submitter clinical testing p.Arg122Cys (CGC>TGC): c.364 C>T in exon 6 of the RYR2 gene (NM_001035.2). A variant of unknown significance has been identified in the RYR2 gene. The R122C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R122C 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 R122C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Although missense mutations in nearby residues have not been reported, R122C is located in the N-terminal domain, a mutation hotspot region of the RYR2 gene (Medeiros-Domingo A et al., 2009). 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 ARRHYTHMIA panel(s).
Invitae RCV000456937 SCV000541661 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 122 of the RYR2 protein (p.Arg122Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 43774). This variant occurs within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). 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. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036735 SCV000060390 uncertain significance not specified 2012-06-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg122Cys varia nt in RYR2 has not been reported in the literature, but has been identified in 1 individual with CPVT; however, this variant did not segregate with disease in t wo affected family members, suggesting that it may not be primarily responsible for disease in that family. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg122Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although segregation studies suggest th at this variant may be benign and not causing disease in isolation, we cannot ru le out that this variant may be contributing to disease.

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