Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000156552 | SCV000206271 | uncertain significance | not specified | 2017-07-19 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp4047Hi s variant in RYR2 has been identified by our laboratory in one Caucasian individ ual with CPVT and segregated with disease in one relative with CPVT, one relativ e with PSVT, and in one relative with suspected CPVT. It was absent from large p opulation studies. Computational prediction tools and conservation analysis sugg est that the p.Asp4047His variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, while there i s some suspicion for a pathogenic role, the clinical significance of the p.Arg40 47His variant is uncertain. |
| Invitae | RCV002516338 | SCV001376863 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2020-02-18 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179754). This sequence change replaces aspartic acid with histidine at codon 4047 of the RYR2 protein (p.Asp4047His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. |
| Gene |
RCV001753547 | SCV002007624 | uncertain significance | not provided | 2019-11-29 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance and reported to segregate with suspected or confirmed CPVT or PSVT in three affected relatives (ClinVar Variant ID# 179754; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect |