Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001591311 | SCV001816136 | 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 cysteine with tryptophan at codon 2363 of the RYR1 protein, p.(Cys2363Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had 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), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.78 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. |
| Labcorp Genetics |
RCV000557457 | SCV000660016 | pathogenic | RYR1-related disorder | 2023-07-17 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 478267). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 30236257). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 2363 of the RYR1 protein (p.Cys2363Trp). |