Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002537074 | SCV000937671 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2018-09-07 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with aspartic acid at codon 3946 of the RYR2 protein (p.Gly3946Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with a history of sudden cardiac arrest (Invitae). This variant has also been reported in an individual with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 19398665). 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.Gly3946 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 19398665, 12093772, 23595086, Invitae), 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. |