ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1201C>T (p.Arg401Cys) (rs193922764)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000610923 SCV000712043 likely pathogenic Malignant hyperthermia susceptibility 2016-07-20 criteria provided, single submitter clinical testing The p.Arg401Cys variant in RYR1 has been reported in 11 individuals with with ma lignant hyperthermia susceptibility and/or minicore myopathy (Davis 2002, Galli 2002, Ruffert 2002, Pietrini 2004, Gillies 2008, Amburgey 2013, Klingler 2014, G illies 2015) and segregated with disease in 3 affected relatives with susceptibi lity to malignant hyperthermia from 2 families (Davis 2002). It was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg401Cys variant may impact protein function (Sato 2013). However, these types of assays may not accurately represent biological function. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Arg401Cys variant is likely pathogenic.
PreventionGenetics,PreventionGenetics RCV000119449 SCV000852278 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing
Invitae RCV000802489 SCV000942323 pathogenic RYR1-Related Disorders 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 401 of the RYR1 protein (p.Arg401Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the heterozyous state in multiple individuals affected with malignant hyperthermia (MH) and segregated with MH in two families (PMID: 12066726, 24433488, 25735680). This variant has also been observed in the compound heterozygous state in multiple individuals affected with RYR1-related myopathy (PMID: 23919265, 28818389). ClinVar contains an entry for this variant (Variation ID: 133029). This variant has been reported to affect RYR1 protein function (PMID: 23459219). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). Other variant(s) that disrupt the p.R401 amino acid residue have been observed in individuals with RYR1-related conditions (PMID: 16163667, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119449 SCV000154356 not provided not provided no assertion provided not provided

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