Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000213932 | SCV000279214 | uncertain significance | not provided | 2016-01-05 | criteria provided, single submitter | clinical testing | The G3657D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G3657D variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G3657D 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. However, this substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Additionally, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants. Finally, the G3657D 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). |
| Ambry Genetics | RCV002450642 | SCV002738569 | uncertain significance | Cardiovascular phenotype | 2021-11-29 | criteria provided, single submitter | clinical testing | The p.G3657D variant (also known as c.10970G>A), located in coding exon 78 of the RYR2 gene, results from a G to A substitution at nucleotide position 10970. The glycine at codon 3657 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002494604 | SCV002777286 | uncertain significance | Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome | 2021-09-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003765446 | SCV004654507 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-07-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3657 of the RYR2 protein (p.Gly3657Asp). This variant is not present in population databases (gnomAD no frequency). 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: 234433). 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. |