Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000148831 | SCV002047606 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-04-06 | 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 glutamic acid with lysine at codon 2404 of the RYR1 protein, p.(Glu2404Lys). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000127, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:19191329). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. An ex vivo assay in lymphoblasts from multiple related individuals showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested (PMID:19191329). 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 three individuals, PP1_Supporting (PMID:19191329). A REVEL score of 0.676 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP1_Supporting. |
| Labcorp Genetics |
RCV001244851 | SCV001418101 | pathogenic | RYR1-related disorder | 2023-07-31 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 161379). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or statin-associated muscle symptoms (PMID: 19191329, 30325262). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs111364296, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2404 of the RYR1 protein (p.Glu2404Lys). |
| All of Us Research Program, |
RCV000148831 | SCV004820906 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-12-18 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 2404 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study on patient-derived lymphoblastoid cells showed this variant increases sensitivity to caffeine but not 4-CmC compared to cells carrying wild-type RYR1 (PMID: 19191329). This variant has been reported in a family affected with malignant hyperthermia susceptibility (PMID: 19191329). This variant has been identified in 9/268418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004700474 | SCV005203295 | uncertain significance | not specified | 2024-07-30 | criteria provided, single submitter | clinical testing | Variant summary: RYR1 c.7210G>A (p.Glu2404Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 237118 control chromosomes. c.7210G>A has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility (Levano_2009). These data indicate that the variant may be associated with disease. It has also been observed in individuals with statin-associated muscle spasms (Isackson_2018) and facioscapulohumeral muscular dystrophy (Erdmann_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36100962, 30325262, 19191329). ClinVar contains an entry for this variant (Variation ID: 161379). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| CSER _CC_NCGL, |
RCV000148831 | SCV000190572 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2014-06-01 | no assertion criteria provided | research |