ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13900G>A (p.Val4634Ile)

gnomAD frequency: 0.00001  dbSNP: rs756310498
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV001823511 SCV002073003 uncertain significance Arrhythmogenic right ventricular dysplasia 2 criteria provided, single submitter clinical testing The missense variant p.V4634I in RYR2 (NM_001035.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge.The p.V4634I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.13900 in RYR2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV005095288 SCV005811875 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2024-10-12 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4634 of the RYR2 protein (p.Val4634Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1339057). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. 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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