ClinVar Genomic variation as it relates to human health

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 glutamine at codon 3903 of the RYR1 protein, p.(Arg3903Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000026, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight 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:20681998, PMID:24433488, PMID:30236257). 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 >0.85 (0.97) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4, PP3_Moderate.

The p.Arg3903Gln variant in RYR1 has been reported in at least 8 individuals with malignant hyperthermia (MH) or malignant hyperthermia susceptibility (MHS) and in 2 individuals with idiopathic hyperCKemia and segregated with MH/MHS in at least 3 affected relatives from 2 families (Galli 2006 PMID: 16835904, Tammaro 2011 PMID: 20681998, Klingler 2014 PMID: 24433488, Miller 2018 PMID: 30236257). In one of the families, this variant was not identified in 2 individuals with MHS but these individuals had another disease causing RYR1 variant, which was not present in the 2 other affected relatives who carried the p.Arg3903Gln variant, suggesting that there may be 2 disease causing variants in this family (Tammaro 2011 PMID: 20681998). The p.Arg3903Gln variant has been identified in 0.003% (2/68036) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with the frequency of MH in the general population. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as likely pathogenic on Aug 26, 2021 by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (ClinVar ID 133017). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP criteria applied: PS4, PP3, PM2_Supporting.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19252784, 16917943, 30236257, 20681998, 24433488, 16835904, 34535181, 19191333, 30611313, 35428369)

For these reasons, this variant has been classified as Pathogenic. 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. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3903 of the RYR1 protein (p.Arg3903Gln). This variant is present in population databases (rs148399313, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and central core disease (PMID: 16835904, 30236257, 30611313). This variant has been reported in individual(s) with autosomal recessive RYR1-related conditions (PMID: 35428369); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 133017).

This missense variant replaces arginine with glutamine at codon 3903 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals and families affected with malignant hyperthermia susceptibility (PMID: 16835904, 19191333, 20681998, 30236257). This variant has been identified in 3/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.