Schematic of the Nav1.3 protein showing pathogenic variants associated with SCN3A-ND

Shown are locations of all missense variants corresponding to disease-associated pathogenic or likely pathogenic variants in SCN3A, with the number of cases indicated in parentheses (). Nav1.3 is formed by four repeated domains (DI-IV), each composed of six transmembrane segments (S1-6), with S4 of each domain mediating voltage sensing and S5-6 forming the ion conducting pore. Variants associated with malformation of cortical development (MCD) with or without epilepsy are indicated with a purple circle, while variants identified in individuals with DEE without MCD are indicated with an orange circle. A blue circle denotes variants identified in people where neuroimaging data was unavailable (Unknown). Note that pathogenic variants appear to be preferentially clustered in S4-6 of DII-IV, with many variants at/near the intracellular S4-5 linker of DII-IV.

DEE = developmental and epileptic encephalopathy; MCD = malformation of cortical development