Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000148790 | SCV001653535 | 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 valine with isoleucine at codon 3840 of the RYR1 protein, p.(Val3840Ile). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00040, 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 without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.648 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. |
| Labcorp Genetics |
RCV000545953 | SCV000659766 | uncertain significance | RYR1-related disorder | 2022-04-02 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 3840 of the RYR1 protein (p.Val3840Ile). This variant is present in population databases (rs140616359, gnomAD 0.03%). This missense change has been observed in individual(s) with a family history of malignant hyperthermia and malignant hyperthermia (PMID: 16732084, 16917943). ClinVar contains an entry for this variant (Variation ID: 133013). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. |
| Mendelics | RCV000148790 | SCV001141072 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-06-02 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000119433 | SCV001785200 | uncertain significance | not provided | 2024-08-22 | criteria provided, single submitter | clinical testing | In silico analysis indicates that this missense variant does not alter protein structure/function; Reported previously in the heterozygous state in an individual with malignant hyperthermia; however parental studies were not performed (PMID: 16732084); This variant is associated with the following publications: (PMID: 25637381, 16917943, 34535181, 35538921, 16732084) |
| Juno Genomics, |
RCV004796023 | SCV005417061 | uncertain significance | Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome | criteria provided, single submitter | clinical testing | PM2_Supporting+PP3+PP2 | |
| Leiden Muscular Dystrophy |
RCV000119433 | SCV000154340 | not provided | not provided | no assertion provided | not provided | ||
| CSER _CC_NCGL, |
RCV000148790 | SCV000190528 | likely benign | Malignant hyperthermia, susceptibility to, 1 | 2014-06-01 | no assertion criteria provided | research |