ClinVar

Description

The p.G2043W substitution in the COL7A1 gene has been reported previously as a pathogenic variantand is the same position as the most common recurrent autosomal dominant COL7A1 variant (G2043R)in DDEB patients (Varki et al 2006). The p.G2043W variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The p.G2043W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this substitution is probably damaging to the protein structure/function as it occurs at the first Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII protein. Glycine substitution variants in this region of the collagen VII protein will destabilize the collagen triplehelix resulting in anchoring fibrils that are unstable and result in poor anchoring off the basementmembrane to the underlying dermis. Missense variants at the same residue (G2043R, G2043E) andnearby residues (G2031S, G2037R) have been reported in the Human Gene Mutation Database inassociation with DEB (Stenson et al., 2009), supporting the functional importance of this region of theprotein. We interpret G2043W in COL7A1 as a pathogenic variant.