ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14918C>T (p.Pro4973Leu) (rs146876145)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148804 SCV000190542 likely pathogenic Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119571 SCV000225123 likely pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000119571 SCV000596912 likely pathogenic not provided 2015-09-25 criteria provided, single submitter clinical testing
Invitae RCV000554319 SCV000659864 likely pathogenic RYR1-Related Disorders 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 4973 of the RYR1 protein (p.Pro4973Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs146876145, ExAC 0.02%). This variant has been reported in the compound heterozygous state in an individual affected with centronuclear myopathy (PMID: 25957634) and has been reported to segregate with malignant hyperthermia in the heterozygous state in three families (PMID: 12208234, 12411788). In one of these families, a separate variant in CACNA1S (p.Arg1086His) also segregated with disease (PMID: 12411788). ClinVar contains an entry for this variant (Variation ID: 133098). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000605381 SCV000711662 likely pathogenic Malignant hyperthermia susceptibility 2017-07-10 criteria provided, single submitter clinical testing The p.Pro4973Leu variant in RYR1 has been reported in 2 individuals with maligna nt hyperthermia susceptibility phenotype (MHS), 2 individuals with malignant hyp erthermia equivocal phenotype (MHE) and 1 individual with centronuclear myopathy and segregated with disease in at least 3 affected relatives (MHS:1, MHE:2) fro m 2 families (Galli 2002, Monnier 2002, Monnier 2005, Brandom 2013, Fattori 2015 ). This variant has been reported in ClinVar (Variation ID 133098).This variant has also been identified in 3/33582 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs146876145). This f requency is low enough to be consistent with the frequency of malignant hyperthe rmia in the general population. Computational prediction tools and conservation analysis suggest that the p.Pro4973Leu variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical signifi cance, the p.Pro4973Leu variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PP3, PP1_Supporting.
Leiden Muscular Dystrophy (RYR1) RCV000119571 SCV000154478 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119571 SCV000852469 likely pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000148804 SCV000803505 likely pathogenic Malignant hyperthermia, susceptibility to, 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Malignant hyperthermia 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:12411788) (PMID:12208234). PM2 => Present in ExAC with allele frequency compatible with incidence of malignant hyperthermia in the general population. PS3 => Well-established functional studies show a deleterious effect (PMID:28687594).

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