Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225218 | SCV002503797 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace threonine with alanine at codon 214 of the RYR1 protein (p.Thr214Ala). The threonine residue is low to moderately conserved (100 vertebrates, UCSC), and is located in the MH1 N-terminal mutational hot spot (PM1; PMID: 30406384). There is a small physicochemical difference between threonine and alanine. The variant is present in a single individual in a large population cohort (PM2; rs769650157, 1/251,416 alleles in gnomAD v2.1), and has not been reported in the relevant literature or as a European Malignant Hyperthermia Group diagnostic mutation. Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). A different missense change at the same amino acid residue (p.Thr214Met) has been identified in multiple malignant hyperthermia susceptible cases (PMID: 25658027). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2. |
| Fulgent Genetics, |
RCV002496167 | SCV002787042 | uncertain significance | Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome | 2021-08-12 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV002225218 | SCV004820718 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-07-10 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with alanine at codon 214 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 1/251416 chromosomes 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. |