ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12272C>T (p.Ala4091Val)

dbSNP: rs794728783
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002279938 SCV000235197 pathogenic not provided 2022-08-19 criteria provided, single submitter clinical testing Has been reported in individuals with CPVT seen at GeneDx and in published literature (Hayashi et al., 2009; Jabbari et al., 2013; Guidicessi et al., 2019; Gerber et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19632629); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24025405, 19398665, 26256814, 26132555, 31112425, 19632629, 32553227)
Invitae RCV002515335 SCV003524140 pathogenic Catecholaminergic polymorphic ventricular tachycardia 1 2023-11-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4091 of the RYR2 protein (p.Ala4091Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant catecholaminergic polymorphic ventricular tachycardia (PMID: 19398665, 26256814, 31112425). ClinVar contains an entry for this variant (Variation ID: 201325). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Medical Research Institute, Tokyo Medical and Dental University RCV000190127 SCV000221977 uncertain significance Long QT syndrome no assertion criteria provided research

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