Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000148822 | SCV001810080 | 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 2214 of the RYR1 protein, p.Val2214Ile. The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00016, 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), however, the high MAF in the AFR population in gnomAD precludes the use of PS4 (PMID:11575529). 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 0.798 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. |
| Eurofins Ntd Llc |
RCV000119666 | SCV000230502 | uncertain significance | not provided | 2014-11-15 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000528915 | SCV000660002 | pathogenic | RYR1-related disorder | 2023-11-20 | 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 2214 of the RYR1 protein (p.Val2214Ile). This variant is present in population databases (rs193922795, gnomAD 0.02%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (PMID: 11575529; Invitae). ClinVar contains an entry for this variant (Variation ID: 133168). 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. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002498551 | SCV002778515 | 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 | 2021-08-25 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV003988828 | SCV004805477 | uncertain significance | Central core myopathy | 2024-03-25 | criteria provided, single submitter | research | |
| Leiden Muscular Dystrophy |
RCV000119666 | SCV000154573 | not provided | not provided | no assertion provided | not provided | ||
| CSER _CC_NCGL, |
RCV000148822 | SCV000190561 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2014-06-01 | no assertion criteria provided | research |