Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001592838 | SCV001815843 | uncertain significance | Malignant hyperthermia of anesthesia | 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 threonine with isoleucine at codon 4853 of the RYR1 protein, p.(Thr4853Ile). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result without a clear MH event (PMID: 16244682), PS4 not met. 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_Supporting (PMID: 21118704). A REVEL score >0.85 (0.982) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. |
| Labcorp Genetics |
RCV000655602 | SCV000777533 | pathogenic | RYR1-related disorder | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 4853 of the RYR1 protein (p.Thr4853Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital myopathy and/or malignant hyperthermia (PMID: 16244682, 23394784; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 544455). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV000721383 | SCV000852431 | likely pathogenic | not provided | 2016-03-31 | criteria provided, single submitter | clinical testing |