Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002338396 | SCV002641136 | uncertain significance | Cardiovascular phenotype | 2018-11-26 | criteria provided, single submitter | clinical testing | The p.E1724V variant (also known as c.5171A>T), located in coding exon 37 of the RYR2 gene, results from an A to T substitution at nucleotide position 5171. The glutamic acid at codon 1724 is replaced by valine, an amino acid with dissimilar properties. An alternate amino acid substitution, p.E1724K c.5170G>A has been detected in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT), and was reported to segregate with symptoms in an additional relative in two families (Postma AV et al. J. Med. Genet., 2005 Nov;42:863-70; Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517; Kawata H et al. Circ. J., 2016 Aug;80:1907-15). 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. |
| Labcorp Genetics |
RCV005096747 | SCV005731339 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2024-07-16 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1724 of the RYR2 protein (p.Glu1724Val). 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: 1745804). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. This variant disrupts the p.Glu1724 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16272262, 22787013, 26114861, 28237968, 29032884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |