EPCO-40. PREVALENCE OF PATHOGENIC <i>TSC1</i> AND <i>TSC2</i> VARIANTS IN THE KOREAN POPULATION BASED ON LARGE-SCALE GENOMIC DATA

Abstract TSC1 and TSC2 encode hamartin and tuberin, key regulators of the mTOR pathway that controls cell growth and proliferation. Germline pathogenic variants in these genes cause tuberous sclerosis complex (TSC), a multisystem disorder frequently associated with neurological tumors such as subependymal giant cell astrocytomas (SEGAs) and cortical tubers. However, population-level data on TSC1 and TSC2 variant frequencies remain scarce, particularly in East Asian populations. We analyzed exome sequencing data from 125,748 individuals in the Genome Aggregation Database (gnomAD), including 9,197 East Asians, as well as Korean-specific datasets comprising 5,305 individuals from the Korean Variant Archive (KOVA), 3,617 from Korea4K, and 1,722 from the Korean Reference Genome Database (KRGDB). Variants in TSC1 and TSC2 were annotated and classified according to ACMG/AMP and ClinGen guidelines, focusing on pathogenic and likely pathogenic variants. The global carrier frequency was estimated at 0.005% for TSC1 and 0.007% for TSC2. Among populations, the TSC1 carrier frequency was highest in Ashkenazi Jewish (0.040%) followed by East Asians (0.011%). TSC2 carrier frequency was also elevated in East Asians (0.011%), second only to Latinos (0.012%). In the integrated Korean dataset (n = 12,553), the estimated carrier frequencies were 0.032% for TSC1 and 0.032% for TSC2, indicating a notably higher prevalence in Koreans compared to other East Asian subgroups. This study provides the first comprehensive, population-based estimate of TSC1 and TSC2 pathogenic variant frequencies in Koreans. These findings highlight a potentially elevated burden of hereditary TSC in this population and underscore the need for population-specific genomic data to support accurate risk assessment, early detection, and clinical management of neuro-oncologic manifestations associated with TSC.