ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.721C>T (p.Arg241Cys)

gnomAD frequency: 0.00004  dbSNP: rs751622747
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000820196 SCV000960897 uncertain significance RYR1-related disorder 2022-08-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 241 of the RYR1 protein (p.Arg241Cys). This variant is present in population databases (rs751622747, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 662533). 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 RYR1 protein function. 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.
GeneDx RCV001759605 SCV001985706 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002507438 SCV002817065 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 2021-10-27 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001759605 SCV003810481 uncertain significance not provided 2019-07-17 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002822 SCV004820721 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-06-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 241 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 3/251460 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.

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