ACMG/AMP variant classification specifications from the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel.
Publication/Presentation Date
6-1-2026
Abstract
PURPOSE: Pathogenic variants in SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B have been associated with a spectrum of epilepsy and neurodevelopmental disorders. We created a ClinGen Variant Curation Expert Panel and adapted the ACMG/AMP recommendations for sequence variant classification for each of these genes.
METHODS: We convened a multidisciplinary panel and evaluated current recommendations for applicability. We generated specifications based on clinical, bioinformatic, and functional data, and piloted modified criteria on 37 variants.
RESULTS: Our pilot consisted of variants across the spectrum of prior classifications (pathogenic, benign and variant of uncertain significance) and range of variant types (missense, nonsense, frameshift, and intronic). Through iterative discussion, our specifications notably include 1) importance of epilepsy syndrome classification and phenotyping, 2) optimization of population thresholds (BS1, BA1), 3) use of paralogous genes when considering prior pathogenic variants at corresponding positions (PS1, PM5), and 4) guidance on interpreting functional data (PS3), among other modifications.
CONCLUSION: Adopting modified variant curation specifications for SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B optimizes variant classification based on evolving knowledge of sodium channel genes. Obtaining an accurate genetic diagnosis has both clinical and personal utility for individuals living with epilepsy and neurodevelopmental disorders, particularly as precision therapeutics become more widely available.
First Page
102615
Last Page
102615
ISSN
1530-0366
Published In/Presented At
Smith, L., Bonkowski, E., Prentice, A., Cohen, S., Lusk, L., Parthasarathy, S., Burns, B., Butler, E., Chen, Y., Dady, K., Dugger, S., Ing, A., Lassiter, R., Lewis-Smith, D., Mulhern, M., Nguyen, J. N. H., Olival, J., Sajan, S. A., Thompson, C. H., George, A. L., Jr, … Mefford, H. C. (2026). ACMG/AMP variant classification specifications from the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel. Genetics in medicine : official journal of the American College of Medical Genetics, 102615. Advance online publication. https://doi.org/10.1016/j.gim.2026.102615
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
42227234
Department(s)
Department of Pediatrics
Document Type
Article