Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002516214 | SCV000943027 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4588 of the RYR2 protein (p.Ile4588Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RYR2-related disease (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 235052). 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. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002378958 | SCV002698135 | uncertain significance | Cardiovascular phenotype | 2018-12-07 | criteria provided, single submitter | clinical testing | The p.I4588T variant (also known as c.13763T>C), located in coding exon 94 of the RYR2 gene, results from a T to C substitution at nucleotide position 13763. The isoleucine at codon 4588 is replaced by threonine, an amino acid with some similar properties. 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. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223875 | SCV000280446 | uncertain significance | not specified | 2015-07-24 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ile4588Thr (I4588T; c.13763 T>C) in RYR2 The variant is completely novel. As of October 23, 2013, it has not been reported in the literature either as a disease-causing mutation or as a benign variant. Ile4588Thr is a non-conservative amino acid substitution from a nonpolar Isoleucine residue to a polar Threonine. The Isoleucine at position 4588 is absolutely conserved across 9 species of vertebrates for which data are available, as are two residues to either side. In silico analysis with PolyPhen2 predicts this change to be “possibly damaging” to the structure/function of the protein (score of 0.905). GeneDx noted in its report that this variant is in a putative transmembrane domain, where no other pathogenic mutations had been reported to their knowledge as of 2010. The NYU arrhythmia database agrees that there are no nearby mutations. However, residue 4588 does fall within one of the 3 mutation “hotspots” for CPVT (the third “hotspot”, which is in the channel region between residues 3778-4959). In total the variant has not been seen in >6100 controls and individuals from publicly available population datasets as of October 23, 2013. No variation at this residue is listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4000 Caucasian and ~1800 African American individuals. No variation at this residue is found in 1000 Genomes or dbSNP (http://browser.1000genomes.org/index.html). GeneDx did not detect this variant in up to 300 controls of Caucasian and African American ancestry. These controls, however, are not ancestry-matched to our Hispanic patient. |