ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1727A>G (p.His576Arg)

dbSNP: rs794728818
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182865 SCV000235253 uncertain significance not provided 2019-05-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV002516905 SCV002259297 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2021-08-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 576 of the RYR2 protein (p.His576Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. 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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