ClinVar

Description

The E100K missense variant in the GJB3 gene has been reported previously in association with Erythrokeratodermia Variabilis (EKV) in an individual who was homozygous for the variant (Terrinoni et al., 2004). Heterozygous relatives were unaffected in that family. E100K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E100K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (R101Q) havs been reported in the Human Gene Mutation Database in association with EKV (Stenson et al., 2014). Therefore, we consider this variant to be likely pathogenic for autosomal recessive EKV.