Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001810794 | SCV002048366 | uncertain significance | not provided | 2021-10-05 | criteria provided, single submitter | clinical testing | The RYR2 c.6519G>T; p.Glu2173Asp variant (rs368920731), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.0008% (2/248,792 alleles) in the Genome Aggregation Database. The glutamic acid at codon 2173 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.531). Due to limited information, the clinical significance of the p.Glu2173Asp variant is uncertain at this time. |
| Color Diagnostics, |
RCV001806267 | SCV002052415 | uncertain significance | Cardiomyopathy | 2021-04-06 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 2173 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248792 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 | RCV002542331 | SCV002314448 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2021-02-03 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with RYR2-related conditions. 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. This variant is present in population databases (rs368920731, ExAC 0.002%). This sequence change replaces glutamic acid with aspartic acid at codon 2173 of the RYR2 protein (p.Glu2173Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. |
| Ambry Genetics | RCV002361062 | SCV002658306 | uncertain significance | Cardiovascular phenotype | 2021-11-08 | criteria provided, single submitter | clinical testing | The p.E2173D variant (also known as c.6519G>T), located in coding exon 42 of the RYR2 gene, results from a G to T substitution at nucleotide position 6519. The glutamic acid at codon 2173 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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. |