ClinVar Miner

Submissions for variant NM_000094.4(COL7A1):c.6082G>A (rs762162799)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000435332 SCV000516585 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing The G2028R variant in the COL7A1 gene has been reported previously in both autosomal dominant and autosomal recessive dystrophic epidermolysis bullosa (DEB), including one individual with DDEB in whom the G2028R variant occurred de novo (Lee et al., 2000; Murata et al., 2000; Nakamura et al., 2004; Varki et al., 2007; Lucky et al., 2018). This variant is not observed in large population cohorts (Lek et al., 2016). The G2028R 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 analyses, including protein predictors and evolutionary conservation, support a deleterious effect, as this substitution occurs at a Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII protein. Other missense variants in the same Glycine residue (G2028W, G2028A, G2028E) have also been reported in the Human Gene Mutation Database in association with DEB, supporting the functional importance of this Glycine position (Stenson et al., 2014). Glycine substitutions in this region of the protein destabilize the COLVII triple helix yielding fragile and unstable anchoring fibrils that are unable to adequately anchor the basement membrane of the epidermis to the dermis, resulting in skin fragility. We interpret G2028R as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763113 SCV000893655 pathogenic Recessive dystrophic epidermolysis bullosa; Pretibial epidermolysis bullosa; Dominant dystrophic epidermolysis bullosa with absence of skin; Transient bullous dermolysis of the newborn; Epidermolysis bullosa pruriginosa; Nail disorder, nonsyndromic congenital, 8; Generalized dominant dystrophic epidermolysis bullosa 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000435332 SCV001246190 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Biomedical Innovation Departament, CIEMAT RCV001352760 SCV001547342 pathogenic Dystrophic epidermolysis bullosa 2019-01-28 criteria provided, single submitter research
Invitae RCV000435332 SCV001578935 pathogenic not provided 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2028 of the COL7A1 protein (p.Gly2028Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant and autosomal recessive dystrophic epidermolysis bullosa (PMID: 10836608, 30280950, 19665875, 18429782). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 379476). 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. 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. For these reasons, this variant has been classified as Pathogenic.

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