ClinVar Genomic variation as it relates to human health

Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11142768, 30293248, 16971478, 21448560, 29334134, 31001817, 33587123, 30280950, 10836608, 15113589)

In dominant COL7A1 associated DEB, identified pathogenic variants are typically heterozygous glycine substitutions within the type VII collagen triple helix (PMID: 18558993, 11260189). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in individuals, and appears de novo in one individual, with clinical features associated with dominant epidermolysis bullosa (PMID: 10836608, 30293248, 21448560). Computational tools yielded predictions that this amino acid change, which occurs within the type VII collagen triple helix region, may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL7A1 protein function. ClinVar contains an entry for this variant (Variation ID: 379476). This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive dystrophic epidermolysis bullosa (PMID: 10836608, 18429782, 19665875, 30280950). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2028 of the COL7A1 protein (p.Gly2028Arg).

COL7A1: PM1:Strong, PM2, PM5, PS4:Moderate, PP3

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dystrophic epidermolysis bullosa (DEB) (OMIM, PMID: 31670143). (I) 0108 - This gene is associated with both recessive and dominant disease. The spectrum of DEB associated with this gene can be either dominant or recessive. Dominant inheritance (DDEB; MIM#131750) is typically associated with milder phenotypes, whereas recessive inheritance (RDEB; MIM#226600) is usually observed in more severe cases (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity ranges from involving only nails to generalized and severe blistering and scarring (PMID: 31670143). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional triple repeat region of the collagen domain (NCBI). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The variant p.(Gly2028Trp) has been reported both as monoallelic and biallelic in association with epidermolysis bullosa dystrophica (DEB) (PMID: 21448560). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with DEB, both monoallelic and biallelic, as well as in association with epidermolysis bullosa pruriginosa and nails only (ClinVar, PMIDs: 21448560, 31001817, 33587123). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign