ClinVar Genomic variation as it relates to human health

The c.5584G>T variant in SCN3A is a missense variant predicted to case the substitution of glycine by cysteine at amino acid 1862 (p.Gly1862Cys). The highest population minor allele frequency in gnomAD v.2 is 8.2% (2915/35374 alleles) in the Latino population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.3%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.808 (PP3_Moderate). Although there are both pathogenic and benign types of evidence for this variant, the high frequency of this variant in gnomAD strongly supports a benign classification, and the only evidence in support of pathogenicity is based on a computational predictor that should not override the high population frequency, which precludes this variant from being pathogenic for a rare disease. In summary, this variant meets the criteria to be classified as Benign for autosomal dominant developmental and epileptic encephalopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1; 6/27/2023).