Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182723 | SCV000235106 | uncertain significance | not provided | 2016-09-22 | criteria provided, single submitter | clinical testing | p.Asn1503Asp (AAT>GAT): c.4507 A>G in exon 34 of the RYR2 gene (NM_001035.2). The Asn1503Asp variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn1503Asp results in a non-conservative amino acid substitution of neutral, polar Asparagine with a negatively charged Aspartic acid at a position that is not uniformly conserved across species. As result, in silico analysis predicts Asn1503Asp likely has a benign effect on the protein structure/function. The NHLBI ESP Exome Variant Server reports Asn1503Asp was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The Asn1503Asp variant does not occur in any of the RYR2 mutation hot spots and no mutations have been reported in nearby residues to date (Medeiros-Domingo A et al., 2009). In summary, the clinical significance of the Asn1503Asp variant in the RYR2 gene is currently unknown.The variant is found in ARVC,POSTMORTEM panel(s). |
| Ambry Genetics | RCV000621042 | SCV000737689 | uncertain significance | Cardiovascular phenotype | 2016-09-02 | criteria provided, single submitter | clinical testing | The p.N1503D variant (also known as c.4507A>G), located in coding exon 34 of the RYR2 gene, results from an A to G substitution at nucleotide position 4507. The asparagine at codon 1503 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs794728736, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6343 samples (12686 alleles) with coverage at this position. This amino acid position is well 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. |
| Invitae | RCV002516880 | SCV002589675 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-03-26 | 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: 201247). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs794728736, gnomAD 0.007%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1503 of the RYR2 protein (p.Asn1503Asp). |