ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12599A>G (p.Asn4200Ser)

dbSNP: rs199660276
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000537764 SCV000659791 uncertain significance RYR1-related disorder 2021-08-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 4200 of the RYR1 protein (p.Asn4200Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with axial myopathy (PMID: 23478172). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Athena Diagnostics RCV000992763 SCV001145289 uncertain significance not provided 2018-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000992763 SCV001992193 uncertain significance not provided 2019-04-22 criteria provided, single submitter clinical testing Reported as heterozygous in an individual with axial myopathy, in whom a variant in the MYH7 gene was also detected and believed to be causative; a healthy parent was also heterozygous for the RYR1 variant (Clarke et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23478172)
Fulgent Genetics, Fulgent Genetics RCV002476207 SCV002786797 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 2021-10-29 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000537764 SCV004111533 uncertain significance RYR1-related disorder 2023-05-09 criteria provided, single submitter clinical testing The RYR1 c.12599A>G variant is predicted to result in the amino acid substitution p.Asn4200Ser. This variant was reported in a patient with axial myopathy; however, this patient had additional variants in other candidate genes (Proband 2 in Clarke et al. 2013. PubMed ID: 23478172). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV003999484 SCV004816228 uncertain significance Malignant hyperthermia, susceptibility to, 1 2022-12-07 criteria provided, single submitter clinical testing

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