Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182769 | SCV000235155 | uncertain significance | not provided | 2014-04-15 | criteria provided, single submitter | clinical testing | p.Ala2818Val (GCC>GTC): c.8453 C>T in exon 57 of the RYR2 gene (NM_001035.2). The A2818V variant has not been published as a mutation or as a benign polymorphism to our knowledge. The A2818V variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the A2818V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with arrhythmia and the variant is not located in any of the RYR2 mutation hot spots (Medeiros-Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). |
| Invitae | RCV003638637 | SCV004388397 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-12-21 | criteria provided, single submitter | clinical testing | 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. 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 not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 201286). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2818 of the RYR2 protein (p.Ala2818Val). |