Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001450006 | SCV001653556 | likely benign | Malignant hyperthermia of anesthesia | 2021-03-16 | 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 arginine with serine at codon 4136 of the RYR1 protein, p.(Arg4136Ser). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000349, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with myopathy that was MHS, this variant was also present in the father who was MHN by IVCT, PS4 not met, BS2_Moderate (PMID: 12208234). 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 0.783 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS2_Moderate. |
| Prevention |
RCV000119460 | SCV000852294 | uncertain significance | not provided | 2016-04-27 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001854578 | SCV002270872 | likely pathogenic | RYR1-related disorder | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 4136 of the RYR1 protein (p.Arg4136Ser). This variant is present in population databases (rs193922849, gnomAD 0.004%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 12208234). ClinVar contains an entry for this variant (Variation ID: 133037). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Fulgent Genetics, |
RCV002498546 | SCV002805508 | likely benign | Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome | 2021-09-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000119460 | SCV005080073 | uncertain significance | not provided | 2024-03-01 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12208234, 16835904, 34535181) |
| Leiden Muscular Dystrophy |
RCV000119460 | SCV000154367 | not provided | not provided | no assertion provided | not provided |