Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001580438 | SCV001810127 | 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 glycine with arginine at codon 2130 of the RYR1 protein, p.Gly2130Arg. The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000055, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual described as having a malignant hyperthermia (MH) reaction without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4 was not implemented (PMID:18063506). 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 >0.85 (0.894) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. |
| Fulgent Genetics, |
RCV002477306 | SCV002781229 | uncertain significance | Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome | 2021-11-15 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003591685 | SCV004280387 | uncertain significance | RYR1-related disorder | 2023-08-22 | 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 2130 of the RYR1 protein (p.Gly2130Arg). This variant is present in population databases (rs193922789, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of malignant hyperthermia (PMID: 18063506). ClinVar contains an entry for this variant (Variation ID: 133158). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Gene |
RCV000119651 | SCV005080419 | likely pathogenic | not provided | 2024-06-28 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26779337, 12668474, 33767344, 18063506) |
| Leiden Muscular Dystrophy |
RCV000119651 | SCV000154558 | not provided | not provided | no assertion provided | not provided |