Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000210014 | SCV002570143 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2022-09-08 | 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 aspartic acid with glutamic acid at codon 3986 of the RYR1 protein, p.(Asp3986Glu). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had 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), PS4 (PMID:30236257; PMID:23558838). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID: 28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in four individuals/families, PP1_Supporting (PMID:28403410). A REVEL score of 0.763 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Variant of Unknown Significance (PMID: 29300386). Criteria implemented: PS4, BS3_Supporting, PP1. |
| Biesecker Lab/Clinical Genomics Section, |
RCV000210014 | SCV000265745 | pathogenic | Malignant hyperthermia, susceptibility to, 1 | 2013-07-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV000531152 | SCV000659782 | pathogenic | RYR1-related disorder | 2022-03-13 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects RYR1 function (PMID: 19648156, 23558838). 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: 133026). This missense change has been observed in individuals with malignant hyperthermia (PMID: 16917943, 19648156, 23558838, 24195946, 25658027). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 3986 of the RYR1 protein (p.Asp3986Glu). For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV000119446 | SCV000852276 | likely pathogenic | not provided | 2013-11-22 | criteria provided, single submitter | clinical testing | |
| RYR1 database | RCV000119446 | SCV000154353 | not provided | not provided | no assertion provided | not provided |