ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.7160C>T (p.Ala2387Val) (rs794728754)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182758 SCV000235143 likely pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The A2387V variant that is likely pathogenic was identified in the RYR2 gene. This variant has previously been published in association with CPVT (Haugaa et al., 2010; Kawamura et al., 2013). In addition, this variant has been observed in one other unrelated individual referred for arrhythmia genetic testing at GeneDx. The A2387V variant was absent from 400 Japanese control alleles (Kawamura et al., 2013) and was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants affecting the same residue (A2387P, A2387T) and nearby residues (N2386I, Y2392C, A2394G) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the A2387V variant is located in the central domain, one of the three hot-spot regions of the RYR2 gene where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). However, the A2387V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the A2387V variant.Therefore, this variant is likely pathogenic.
Invitae RCV000798351 SCV000937964 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2387 of the RYR2 protein (p.Ala2387Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 23595086, 20106799, 28237968). ClinVar contains an entry for this variant (Variation ID: 201277). 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 and their clinical significance is uncertain. This variant disrupts the p.Ala2387 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16188589, 28600387, 19398665, 28237968), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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