ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14582G>A (p.Arg4861His) (rs63749869)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000786530 SCV000925352 drug response desflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786621 SCV000925443 drug response enflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786622 SCV000925444 drug response halothane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786623 SCV000925445 drug response isoflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786624 SCV000925446 drug response methoxyflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786625 SCV000925447 drug response sevoflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786626 SCV000925448 drug response succinylcholine response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
GeneDx RCV000119533 SCV000329656 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing The R4861H missense variant in the RYR1 gene has been reported multiple times in association with autosomal dominant central core disease (Monnier et al., 2001; Davis et al., 2003; Kossugue et al., 2007; RYR1 LOVD). Additionally, muscle histology identified central cores in affected individuals (Monnier et al., 2001; Maggi et al., 2013). Functional studies demonstrate that R4861H significantly alters intracellular calcium homeostasis (Tilgen et al., 2001). The R4861H variant is not observed in large population cohorts (Lek et al., 2016). The R4861H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, missense variants at the same position (R4861C) and in nearby residues have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R4861H as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000119533 SCV000596914 pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing
Invitae RCV000534187 SCV000659854 pathogenic RYR1-Related Disorders 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 4861 of the RYR1 protein (p.Arg4861His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a commonly causative mutation in multiple individuals and families affected with central core disease (PMID: 16621918, 12565913, 25521991, 11709545, 23394784). This variant has also been reported in an individual affected with malignant hyperthermia (PMID: 23558838). Experimental studies have shown that this variants affects calcium homeostasis in vitro (PMID: 11741831). This missense change is located in the C-terminal mutational hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations have been found (PMID: 16084090). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000119533 SCV000852433 pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000119533 SCV000920473 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851296 SCV000993580 pathogenic Malignant hyperthermia, susceptibility to, 1 2018-09-11 criteria provided, single submitter research
OMIM RCV000013852 SCV000034099 pathogenic Myopathy, Central Core 2008-01-08 no assertion criteria provided literature only
OMIM RCV000013853 SCV000034100 pathogenic Neuromuscular disease, congenital, with uniform type 1 fiber 2008-01-08 no assertion criteria provided literature only
Leiden Muscular Dystrophy (RYR1) RCV000119533 SCV000154440 not provided not provided no assertion provided not provided

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