Submissions for variant NM_001035.3(RYR2):c.7420A>G (p.Arg2474Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003527196	SCV004292014	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2024-04-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2474 of the RYR2 protein (p.Arg2474Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (PMID: 23595086). 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%. This variant disrupts the p.Arg2474 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11208676, 18483626, 30403697). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV004701725	SCV005201505	pathogenic	not provided	2024-03-07	criteria provided, single submitter	clinical testing	Reported in a Japanese patient with CPVT in the published literature (PMID: 23595086); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29434162, 32152366, 23595086, 22828895, 11208676)