ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10529G>A (p.Arg3510His) (rs375947003)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182787 SCV000235173 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The R3510H variant has been reported in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017). The R3510H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). However, the R3510H 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 only conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the R3510H 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 RCV000821400 SCV000962155 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 3510 of the RYR2 protein (p.Arg3510His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs375947003, ExAC 0.002%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201303). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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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