SCN4A Channelopathies: From Disease Mechanisms to Variant Interpretation.

SCN4A encodes the skeletal-muscle voltage-gated sodium channel NaV1.4. Pathogenic variation in this gene produces fundamentally different disease mechanisms, including dominant alpha-pore gain of function, dominant S4 gating-pore currents, and reduced channel availability, with severe biallelic loss of function causing congenital myopathy and fetal hypokinesia. This heterogeneity makes variant interpretation difficult because formal variant classification, the direction of channel dysfunction, and patient-level disease attribution are closely related but distinguishable conclusions. In this review, we synthesize the clinical, genetic, electrophysiological, structural, and functional evidence relevant to SCN4A variant interpretation, with particular attention to missense variants of uncertain significance. We examine how inheritance, channel topology, phenotype, population data, segregation, RNA evidence, regional and residue-level context, and mechanism-matched functional assays can be integrated within the ACMG/AMP framework. Published pathogenic-enriched regions, gnomAD regional missense constraint, and same-residue observations may contribute to variant interpretation when the requirements of an applicable ACMG/AMP criterion are met; when they have not been specifically validated or calibrated for SCN4A, they are best used as contextual information to prioritize additional evidence generation. Based on this literature, we organize these evidence domains into a practical phenotype-first, mechanism-informed workflow for SCN4A variant interpretation. This workflow is not intended as an alternative to or extension of ACMG/AMP but as an SCN4A-specific application of established variant-interpretation principles in a gene associated with multiple inheritance patterns and directionally distinct disease mechanisms. After technical confirmation of a candidate variant, as well as phenotype and inheritance context guide selection of the relevant disease model, appropriately validated functional evidence may contribute directly to ACMG/AMP classification, while functional mechanism and patient-level disease attribution are documented as related but distinguishable interpretative outputs. The same approach applies when a variant is identified through genotype-first sequencing: interpretation should return to deliberate phenotyping, inheritance assessment, electrophysiological characterization, and consideration of the differential diagnosis before disease causality is inferred.