ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu) (rs146876145)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 pathogenic RYR1-Related Disorders 2020-10-27 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 observed to segregate with malignant hyperthermia susceptibility (MHS) in families (PMID: 12411788, 30236257). This variant has also been observed in individuals with autosomal recessive RYR1-related myopathy (PMID: 25957634, 29169929). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 133098). This variant has been reported to affect RYR1 protein function (PMID: 28687594). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000605381 SCV000711662 likely pathogenic Malignant hyperthermia susceptibility 2020-09-01 criteria provided, single submitter clinical testing The p.Pro4973Leu variant in RYR1 has been reported in 4 heterozygous individuals with malignant hyperthermia susceptible or equivalent, 1 compound heterozygous individual with centronuclear myopathy, and 1 compound heterozygous individual with arthrogryposis multiplex congenita (Galli 2002 PMID: 12208234, Monnier 2002 PMID: 12411788, Monnier 2005 PMID: 16163667, Robinson 2006 PMID: 16917943, Carpenter 2009 PMID: 19825159, Brandom 2013 PMID: 23558838, Fattori 2015 PMID: 25957634, Brackmann 2018 PMID: 29169929, Miller 2018 PMID: 30236257). The variant segregated with disease in at least four affected relatives from at least two families, although one affected relative also carried a second variant, p.Arg1086His in CACNA1S, that segregated in two affected relatives without the p.Pro4973Leu variant in RYR1 (Galli 2002 PMID: 12208234, Monnier 2002 PMID: 12411788). This variant has been reported in ClinVar (Variation ID 133098). The p.Pro4973Leu variant has also been identified in 0.009% (3/34586) of Latino chromosomes by gnomAD ( Computational prediction tools and conservation analysis suggest that the p.Pro4973Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies assaying store overload-induced Ca2+ release (SOICR) from inducible expression of the RYR1 protein with the p.Pro4973Leu substitution in HEK293 cells support that the variant may impact protein function (Chen 2017 PMID: 28687594). Furthermore, this variant is located within one of the RYR1 regions that are considered critical functional domains. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant malignant hyperthermia . ACMG/AMP criteria applied: PM2_Supporting, PP1, PP3, PS3_Supporting, PS4_Supporting, PM1.
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).
PreventionGenetics,PreventionGenetics RCV000119571 SCV000852469 likely pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000148804 SCV001434880 likely pathogenic Malignant hyperthermia, susceptibility to, 1 2018-10-10 criteria provided, single submitter clinical testing This c.14918C>T (p.Pro4973Leu) variant in the RYR1 gene has been reported in multiple individuals with susceptibility to malignant hyperthermia and segregates with disease in several families (PMID 12208234, 12411788, 23558838). This variant was also reported in trans with another pathogenic RYR1 variant in one individual affected with centronuclear myopathy (PMID 25957634). In silico analyses of this conserved variant predict damaging consequences on the RYR1 protein. Therefore, this c.14918C>T (p.Pro4973Leu) variant in the RYR1 gene is classified as likely pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270104 SCV001448930 likely pathogenic Malignant hyperthermia 2019-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000119571 SCV001872859 likely pathogenic not provided 2021-07-13 criteria provided, single submitter clinical testing Reported in individuals in multiple unrelated families who were either malignant hyperthermia susceptible or equivocal by contracture testing (Galli et al., 2002; Monnier et al., 2002; Monnier et al., 2005 [using incorrect nomenclature]; Miller et al., 2018); Observed with a variant on the opposite allele (in trans) in a patient with arthrogryposis multiplex congenita in published literature (Brackmann et al., 2018); Found to be on the same chromsome (in cis) as another RYR1 variant and in trans with a third RYR1 variant in an individual with centronuclear myopathy (Fattori et al., 2015); Published functional studies demonstrate this variant reduces the threshold for store overload-induced calcium release (Chen et al., 2017); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32528171, 20681998, 27535533, 31447099, 16163667, 12411788, 29169929, 12208234, 28687594, 28008009, 23558838, 25957634, 25637381, 30236257)
Leiden Muscular Dystrophy (RYR1) RCV000119571 SCV000154478 not provided not provided no assertion provided not provided
CSER _CC_NCGL, University of Washington RCV000148804 SCV000190542 likely pathogenic Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research
GenomeConnect, ClinGen RCV001249254 SCV001423195 not provided Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy with external ophthalmoplegia no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 10-03-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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