Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522182 | SCV000621044 | uncertain significance | not provided | 2017-09-19 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the RYR2 gene. The c.2300_2301delCGinsGT variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016). The c.2300_2301delCGinsGT variant causes the deletion of two base pairs and insertion of two incorrect base pairs, which leads to the replacement of a serine (S) residue with a cysteine (C) residue at codon position 767, denoted S767C. The S767C variant 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. This amino acid substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, S767C is not 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). Additionally, this variant lacks observation in a significant number of affected individuals, segregation data and functional evidence, all of which would further clarify its role in disease. |
| Color Diagnostics, |
RCV001185068 | SCV001351209 | uncertain significance | Cardiomyopathy | 2023-12-04 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with cysteine at codon 767 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (Takayama 2017). The proband was compound heterozygous for this variant and a splice site variant, RYR2 c.14298+2T>C. The proband's heterozygous parents were asymptomatic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |