ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10700G>A (p.Arg3567His) (rs577371071)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243114 SCV000319882 uncertain significance Cardiovascular phenotype 2017-07-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000519072 SCV000619462 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The R3567H variant has not been published as pathogenic or been reported as benign to our knowledge. The R3567H 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 not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the R3567H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000799166 SCV000938818 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 3567 of the RYR2 protein (p.Arg3567His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs577371071, ExAC 0.06%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 264154). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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