ClinVar Genomic variation as it relates to human health

The heterozygous p.His313Asn variant in KCNB1 was identified by our study in one individual with epileptic encephalopathy. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.His313Tyr, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 33144682, 33057194, 35982159). The number of missense variants reported in KCNB1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant epileptic encephalopathy. ACMG/AMP Criteria applied: PS2_Supporting, PM2_Supporting, PP3, PM5, PP2 (Richards 2015).