Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000013836 | SCV001816165 | pathogenic | Malignant hyperthermia, susceptibility to, 1 | 2021-03-18 | reviewed by expert panel | curation | This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glycine with arginine at codon 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. |
Eurofins Ntd Llc |
RCV000119406 | SCV000225241 | likely pathogenic | not provided | 2014-09-05 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000655541 | SCV000777472 | pathogenic | RYR1-Related Disorders | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the RYR1 protein (p.Gly341Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia (PMID: 8012359, 8825043, 19648156, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12969). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639). For these reasons, this variant has been classified as Pathogenic. |
Preventiongenetics, |
RCV000119406 | SCV000852200 | pathogenic | not provided | 2018-03-15 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000119406 | SCV002019916 | pathogenic | not provided | 2019-05-06 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics Inc | RCV000119406 | SCV002770437 | pathogenic | not provided | 2022-06-23 | criteria provided, single submitter | clinical testing | This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as G342R. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant increased sensitivity to RYR1 activators (PMID:26115329, 9334205, 12732639). |
Color Diagnostics, |
RCV000013836 | SCV004357272 | pathogenic | Malignant hyperthermia, susceptibility to, 1 | 2023-04-18 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 341 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
OMIM | RCV000013836 | SCV000034083 | risk factor | Malignant hyperthermia, susceptibility to, 1 | 1998-10-01 | no assertion criteria provided | literature only | |
Leiden Muscular Dystrophy |
RCV000119406 | SCV000154313 | not provided | not provided | no assertion provided | not provided |