ACMG/AMP variant classification specifications from the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel

Pathogenic variants in SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B have been associated with a spectrum of epilepsy and neurodevelopmental disorders. We created a Clinical Genome Resource variant curation expert panel and adapted the American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations for sequence variant classification for each of these genes.

We convened a multidisciplinary panel and evaluated current recommendations for their applicability. Then, we generated specifications based on clinical, bioinformatic, and functional data and piloted modified criteria on 37 variants.

Our pilot consisted of variants across the spectrum of prior classifications (eg, pathogenic, benign, and variant of uncertain significance) and a range of variant types (eg, missense, nonsense, frameshift, and intronic). Through iterative discussion, our specifications notably include: (1) the importance of epilepsy syndrome classification and phenotyping, (2) optimization of population frequency thresholds, (3) the use of paralogous genes when considering prior pathogenic variants at corresponding positions, and (4) guidance on interpreting functional data, among other modifications.

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.