Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000430239 | SCV000520772 | uncertain significance | not provided | 2017-02-01 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the RYR2 gene. The H2168Q variant has been published in two patients with CPVT (Medeiros-Domingo et al., 2009); however, additional clinical information and functional studies were not included. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H2168Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis suggests that this variant is probably damaging to the protein structure/function. Nevertheless, the H2168Q variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). |
Labcorp Genetics |
RCV002519524 | SCV001211235 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2024-05-21 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2168 of the RYR2 protein (p.His2168Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 19926015, 29453246, 31112425). ClinVar contains an entry for this variant (Variation ID: 381484). 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. |