Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity

Interpreting GABRG2 variants of unknown significance hinders epilepsy precision medicine. Using computer algorithms, our study focused on 156 GABRG2 variants from ClinVar, identifying 10 highly pathogenic variants within the γ2 subunit. Integration with patient mutations and mutagenesis studies locates variants within epileptogenic structural cassettes, aiding phenotype severity and cellular pathology characterization. Our results predict milder phenotypes for 3 N-terminus extracellular domain variants and more severe phenotypes for 7 transmembrane domain variants, linked to cellular pathology with reduced cell surface expression and current. Notably, 4 transmembrane domain variants may distort channel conductance. Our research aligns with ACMG/AMP criteria PP3 and PM1.