Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481805 | SCV000573268 | uncertain significance | not provided | 2017-02-21 | criteria provided, single submitter | clinical testing | The D2274G variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D2274G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D2274G 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 substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant in the same residue (D2274Y) was identified in the heterozygous state in a single individual with multiminicore disease, but the asymptomatic parents were not tested for the variant (Snoek et al., 2015). We interpret D2274G as a variant of uncertain significance. |
| All of Us Research Program, |
RCV004003401 | SCV004822887 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glycine at codon 2274 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. 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. |