ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14200G>A (p.Gly4734Arg)

dbSNP: rs1456212776
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721357 SCV000852396 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing
GeneDx RCV000721357 SCV001986607 uncertain significance not provided 2020-11-18 criteria provided, single submitter clinical testing Not observed 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 RCV002507266 SCV002816524 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 2021-10-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003591773 SCV004305925 uncertain significance RYR1-related disorder 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4734 of the RYR1 protein (p.Gly4734Arg). This variant is not present in population databases (gnomAD no frequency). 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: 590448). 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 with a positive predictive value of 95%. 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.
All of Us Research Program, National Institutes of Health RCV003999822 SCV004830378 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-08-28 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 4734 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 the C-terminal region of the RYR1 protein (a.a. 4,631-4,991) that is considered to be a hotspot for pathogenic variants that may contribute to malignant hyperthermia susceptibility as well as other phenotype(s) (PMID: 21118704). 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). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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