ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4733C>G (p.Pro1578Arg) (rs765351308)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412953 SCV000492410 uncertain significance not specified 2016-12-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The P1578R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 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 P1578R 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 in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the P1578R variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).
Invitae RCV000545583 SCV000637568 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-01-28 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 1578 of the RYR2 protein (p.Pro1578Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs765351308, ExAC 0.01%) but has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 373788). This variant does not occur 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 rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV001184774 SCV001350837 uncertain significance Cardiomyopathy 2019-09-09 criteria provided, single submitter clinical testing

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