Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
CHEO Genetics Diagnostic Laboratory, |
RCV000768788 | SCV000900159 | uncertain significance | Cardiomyopathy | 2016-01-07 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000768788 | SCV001353837 | uncertain significance | Cardiomyopathy | 2020-02-07 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with alanine at codon 3457 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Invitae | RCV002533949 | SCV002286556 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-10-17 | 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 expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 626382). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs544496844, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 3457 of the RYR2 protein (p.Asp3457Ala). |
Ambry Genetics | RCV003362933 | SCV004054104 | uncertain significance | Cardiovascular phenotype | 2023-08-30 | criteria provided, single submitter | clinical testing | The p.D3457A variant (also known as c.10370A>C), located in coding exon 72 of the RYR2 gene, results from an A to C substitution at nucleotide position 10370. The aspartic acid at codon 3457 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |