Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000484014 | SCV000568208 | uncertain significance | not provided | 2017-03-01 | criteria provided, single submitter | clinical testing | The K3997E variant has been reported in one individual from a cohort assessed for CPVT variants in the RYR2 gene (Medeiros-Domingo et al., 2009). However, no patient-specific clinical or segregation data were provided. The K3997E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, K3997E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species and is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, all of which would further clarify pathogenicity. |
| Invitae | RCV003525913 | SCV004292016 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-11-07 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3997 of the RYR2 protein (p.Lys3997Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 19926015; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 419966). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |