ClinVar Miner

Submissions for variant NM_000094.4(COL7A1):c.6127G>A (rs121912836)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414315 SCV000490499 pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The G2043R variant in the COL7A1 gene has been reported previously and is the most common recurrent variant in patients with autosomal dominant dystrophic epidermolysis bullosa (DDEB) (Rouan et al., 1998; Mellerio et al., 1998; Wessagowit et al., 2001; Varki et al., 2007). This variant is not observed in large population cohorts (Lek et al., 2016). The G2043R 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 it occurs at a Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII protein. Other missense variants at the same Glycine codon (G2043W, G2043E) and in nearby Glycine residues (G2040S, G2040D, G2040V, G2046S, G2046D, G2046V) have 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. 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 G2043R as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192885 SCV001361321 pathogenic Pretibial epidermolysis bullosa 2019-09-04 criteria provided, single submitter clinical testing Variant summary: COL7A1 c.6127G>A (p.Gly2043Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243,072 control chromosomes (gnomAD). c.6127G>A has been reported in the literature in multiple individuals affected with Dominant Dystrophic Epidermolysis Bullosa (eg. Christiano_1995, Nishie_2014, Vahidnezhad_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in accumulation of collagen VII in the cytoplasm and increased susceptibility to enzymatic degradation (Nishie_2014). One other clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000018988 SCV001428812 pathogenic Generalized dominant dystrophic epidermolysis bullosa 2019-03-26 criteria provided, single submitter clinical testing
Biomedical Innovation Departament, CIEMAT RCV001352763 SCV001547345 pathogenic Dystrophic epidermolysis bullosa 2018-10-19 criteria provided, single submitter research
OMIM RCV000018988 SCV000039275 pathogenic Generalized dominant dystrophic epidermolysis bullosa 1998-10-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000414315 SCV001742974 pathogenic not provided no assertion criteria provided clinical testing

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