Population Frequency of RYR1 and CACNA1S Variants Associated with Malignant Hyperthermia in the Korean General Population: A KOVA Database Analysis

Background/Objectives: Malignant hyperthermia (MH) is a rare but life-threatening pharmacogenetic disorder. It is most often caused by variants in RYR1 and CACNA1S. The frequency of these variants differs across populations. However, no study has examined this in a general, unselected Korean population. Methods: We screened 81 RYR1 and CACNA1S variants from the European Malignant Hyperthermia Group (EMHG) diagnostic panel (79 RYR1, 2 CACNA1S). We searched for these variants in the KOVA II database, which holds genetic data from 5305 healthy Koreans. Each variant was matched by exact genomic position, reference allele, and alternate allele. Korean allele frequencies for these four confirmed variants were then compared with the Genome Aggregation Database (gnomAD, v4.1.1) using Fisher’s exact test, and confirmed variants were mapped to established RYR1 mutational hotspot regions. Results: Four RYR1 variants were confirmed in the Korean cohort. This gave an overall carrier frequency of 0.075%, or about 1 in 1326 people. All four variants were classified as pathogenic or likely pathogenic in ClinVar/EMHG and all localized to RYR1 mutational hotspots. Three of the four variants showed higher allele frequencies than gnomAD v4.1.1, ranging from 5.0-fold to 19.8-fold; the fourth, c.1565A>G, was not detected in gnomAD v4.1.1 and was significantly enriched relative to it (p = 0.0023). This variant was also reported as a hotspot in Taiwan. Neither of the two EMHG-listed CACNA1S variants (c.3257G>A, c.520C>T) was detected. Conclusions: This is the first population-level report of RYR1 and CACNA1S variant frequency in Koreans. These findings reflect the carrier frequency of EMHG-listed variants rather than the clinical prevalence of MH susceptibility itself. All confirmed variants clustered in known mutational hotspots and were more common than in global databases. These findings provide a baseline reference that may help guide MH genetic testing in the Korean population.