Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002546829 | SCV001531578 | likely pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 366 of the CASQ2 protein (p.Leu366Pro). This variant is present in population databases (rs762153545, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 32693635). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1035127). 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 CASQ2 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Ambry Genetics | RCV002447390 | SCV002732876 | likely pathogenic | Cardiovascular phenotype | 2023-11-17 | criteria provided, single submitter | clinical testing | The p.L366P variant (also known as c.1097T>C), located in coding exon 11 of the CASQ2 gene, results from a T to C substitution at nucleotide position 1097. The leucine at codon 366 is replaced by proline, an amino acid with similar properties. This alteration was found in trans with a likely pathogenic CASQ2 alteration in two siblings with concerns for catecholaminergic polymorphic ventricular tachycardia (CPVT) (Ng K et al. Circulation, 2020 09;142:932-947). Based on internal structure analysis, this alteration was found to be deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Genome- |
RCV003346486 | SCV004050763 | likely pathogenic | Catecholaminergic polymorphic ventricular tachycardia 2 | 2023-04-11 | criteria provided, single submitter | clinical testing |