Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002522777 | SCV000541679 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-07-26 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs536555602, gnomAD 0.007%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3740 of the RYR2 protein (p.Val3740Leu). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 404203). |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786210 | SCV000924931 | uncertain significance | not provided | 2016-06-06 | no assertion criteria provided | provider interpretation | c.11218G>T (p.Val3740Leu) in RYR2 RYR2 has been associated with ARVC, CPVT, and DCM. Given the lack of case data we consider this variant to be of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen the case in a person with DCM who also had a very likely pathogenic variant in LMNA. Testing was done by Invitae The variant has not been reported in the literature. The Invitae report notes, 'This sequence change replaces valine with leucine at codon 3740 of the RYR2 protein (p.Val3740Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine." No paralogue variants have been mapped to this residue in cardiodb.org. It is located in cytoplasmic region of the protein. Cardiodb classifies it as putative benign. The variant was reported online in 1 of 60,037 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). Specifically, the variant was observed in 1 of 4897 African people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). |