Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414102 | SCV000491828 | uncertain significance | not specified | 2016-11-17 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the RYR2 gene. The C1282R variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The C1282R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the C1282R 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).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. |
| Ambry Genetics | RCV003278794 | SCV004009330 | uncertain significance | Cardiovascular phenotype | 2023-04-25 | criteria provided, single submitter | clinical testing | The p.C1282R variant (also known as c.3844T>C), located in coding exon 31 of the RYR2 gene, results from a T to C substitution at nucleotide position 3844. The cysteine at codon 1282 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003766158 | SCV004620066 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-07-28 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1282 of the RYR2 protein (p.Cys1282Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 373249). 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. 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. |