Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001588881 | SCV001816139 | likely pathogenic | 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 lysine with glutamic acid at codon 33 of the RYR1 protein, p.(Lys33Glu). 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 diagnosed with King-Denborough syndrome with a personal history of an MH episode and a positive caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID:18765655). In this individual the variant was determined to be de novo without confirmed parentage PM6_Supporting. 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 (0.92) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic: PM6_Supporting, PS4_Supporting, PM1, PP3_Moderate. |
| Prevention |
RCV000119774 | SCV000852891 | uncertain significance | not provided | 2013-11-19 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003591651 | SCV004297322 | uncertain significance | RYR1-related disorder | 2023-04-11 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 55831). This missense change has been observed in individual(s) with autosomal dominant RYR1-related conditions (PMID: 18765655). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 33 of the RYR1 protein (p.Lys33Glu). |
| OMIM | RCV000049252 | SCV000077505 | pathogenic | King Denborough syndrome | 2008-09-02 | no assertion criteria provided | literature only | |
| Leiden Muscular Dystrophy |
RCV000119774 | SCV000154681 | not provided | not provided | no assertion provided | not provided |