Estimating the Prevalence of Malignant Hyperthermia Susceptibility Based on Causative RYR1 and CACNA1S Variants

Malignant hyperthermia susceptibility (MHS; OMIM 145600, 601887) is a pharmacogenetic condition in which exposure to volatile anesthetics and/or succinylcholine can trigger a potentially life-threatening hypermetabolic crisis of skeletal muscle. MHS is predominantly associated with pathogenic variants in RYR1, whereas CACNA1S contributes a substantially smaller proportion of genetically confirmed cases. Estimating the population prevalence of MHS is challenging because manifestation requires exposure to a triggering agent, penetrance is incomplete, and the evidentiary strength supporting individual variants varies considerably. In this study, MHS-associated RYR1 and CACNA1S variants were compiled from four complementary resources-EMHG, ClinGen MHS VCEP, HGMD, and ClinVar-and subjected to source-specific pathogenicity and phenotype filtering. A total of 13,918 unique reported variants were initially identified. Progressive evidence-based curation generated three nested variant tiers: a high-confidence Expert tier comprising 102 variants; an expanded HGMD-inclusive tier comprising 446 variants; and a full expanded ClinVar-inclusive tier comprising 593 variants. Population allele frequencies were evaluated using gnomAD v4.1.0 and the Russian GDB v1.3.4 database. The high-confidence Expert tier yielded genetically inferred MHS frequencies of approximately 1 in 807 in gnomAD and 1 in 1078 in GDB. Inclusion of HGMD-derived variants increased the corresponding estimates to approximately 1 in 50 and 1 in 104, respectively.