Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182687 | SCV000235066 | uncertain significance | not provided | 2014-07-01 | criteria provided, single submitter | clinical testing | p.Ile559Val (ATC>GTC): c.1675 A>G in exon 17 of the RYR2 gene (NM_001035.2). Approximately 50% of patients with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) are rare (McNally et al., 2009; Napolitano C et al., 2012). The I559V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I559V variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, this substitution occurs at a position that is relatively well conserved across species (V559 accepted in a few species). Furthermore, a missense mutation in a nearby residue (A549V) has been reported in association with CPVT, supporting the functional importance of this region of the protein. Nevertheless, the I559V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). |
| Color Diagnostics, |
RCV001804914 | SCV002053294 | uncertain significance | Cardiomyopathy | 2021-04-05 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 559 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 6/248544 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. |
| Ambry Genetics | RCV002399660 | SCV002714390 | uncertain significance | Cardiovascular phenotype | 2023-08-28 | criteria provided, single submitter | clinical testing | The p.I559V variant (also known as c.1675A>G), located in coding exon 17 of the RYR2 gene, results from an A to G substitution at nucleotide position 1675. The isoleucine at codon 559 is replaced by valine, an amino acid with highly similar properties. 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. |
| Labcorp Genetics |
RCV003765127 | SCV004656545 | likely benign | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-03-09 | criteria provided, single submitter | clinical testing |