Epilepsy-associated Variants of a Single SCN1A Codon exhibit Divergent Functional Properties.

Objective: Pathogenic variants in SCN1A, which encodes the voltage gated sodium channel Na Methods: Whole-cell manual patch-clamp recording was performed on heterologously-expressed Na Results: We describe an individual with early infantile onset DEE associated with SCN1A-I1347T, and identified three additional cases from the literature or ClinVar with distinct variation of the same codon (I1347N, I1347V, I1347F). Functional studies demonstrated mixed gain and loss of function properties for I1347T, I1347V, and I1347F, but complete loss-of-function for I1347N. Structural models suggest important interactions between isoleucine-1347 and the sixth transmembrane helices of domains 3 and 4 that are disrupted most significantly with asparagine replacement at this position (I1347N). Interpretation: Pathogenic variants in SCN1A involving the same codon can produce divergent functional effects. Our findings suggest that predicting specific functional effects of SCN1A variants should not rely heavily on position in the protein.