BACKGROUND: A missense mutation, in the α1c-subunit of voltage-gated L-type Ca2+ channel (LTCC)-coding CACNA1C-E1115K, located in the Ca2+ selectivity site, causes a variety of arrhythmogenic phenotypes. OBJECTIVE: We aimed to investigate the electrophysiological features and pathophysiological mechanisms of CACNA1C-E1115K in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). METHODS: We generated iPSCs from a patient carrying heterozygous CACNA1C-E1115K with overlapping phenotypes of long QT syndrome, Brugada syndrome, and mild cardiac dysfunction. Electrophysiological properties were investigated utilizing iPSC-CMs. We used iPSCs from a healthy subject and an isogenic iPSC line corrected using CRISPR-Cas9-mediated gene editing as controls. The mathematical E1115K-CM model was developed using a human ventricular cell model. RESULTS: Patch-clamp analysis revealed that E1115K-iPSC-CMs exhibited reduced peak Ca2+ current density and impaired Ca2+ selectivity, with an increased permeability to monovalent cations. Consequently, E1115K-iPSC-CMs showed decreased action potential plateau amplitude (APAplateau), longer action potential duration (APD), and a higher frequency of early afterdepolarization compared with controls. In optical recordings examining the anti-arrhythmic drug effect, late Na+ channel current (INaL) inhibitors (mexiletine, GS-458967) shortened APDs specifically in E1115K-iPSC-CMs. AP-clamp using a voltage command obtained from E1115K-iPSC-CMs with lower APAplateau and longer APD confirmed the upregulation of INaL. An in silico study recapitulated the in vitro electrophysiological properties. CONCLUSIONS: Our iPSC-based analysis in CACNA1C-E1115K with disrupted Cav1.2 selectivity demonstrated that the aberrant currents through the mutant channels carried by monovalent cations resulted in specific action potential changes, which increased endogenous INaL; thereby synergistically contributing to the arrhythmogenic phenotype.