ClinVar

Description

The G1534R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G1534R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across class. The G1534R variant 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. In silico analysis predicts this variant 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 triple helix resulting in anchoring fibrils that are fragile and result in poor anchoring off the basement membrane to the underlying dermis . A missense variant in a nearby residue (R1538H) has been reported in the Human Gene Mutation Database in association with DEB (Stenson et al., 2014), supporting the functional importance of this region of the protein. Because this variant has not been reported in the literature, no other affected family members were identified in this study and functional studies have not been performed on this variant, ACMG guidelines do not allow us to designate it as a definitive pathogenic variant. However, because it is a Glycine substitution in the canonical Gly-X-Y region and is replaced by an Arginine at this position, a very common type of pathogenic variant in DEB patients, it is almost certainly pathogenic in this individual. Therefore, at this time this variant is designated likely pathogenic.