ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.7723G>A (p.Gly2575Arg) (rs760891216)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255334 SCV000321513 pathogenic not provided 2016-02-27 criteria provided, single submitter clinical testing The Gly2575Arg pathogenic variant in the COL7A1 gene has been reported previously (Shimizu et al 1996, Pfendner et al 2003, Kern et al., 2006, Saito et al., 2008). The Gly2575Arg variant is reported to affected disulfide bonding between colVII monomers to form the trimer mature col7 fibers Woodley et al., 2008) and also affects the formation of heterotypic trimers more than homotypic ones (Brittingham et al 2005). The Gly2575Arg 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. The Gly2575Arg 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Numerous Glycine substitution variants throughout the COL7A1 gene and missense variants in nearby residues (R2580C) 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. We interpret Gly2575Arg as a pathogenic variant.
Invitae RCV000255334 SCV001589398 pathogenic not provided 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2575 of the COL7A1 protein (p.Gly2575Arg). 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 dystrophic epidermolysis bullosa (PMID: 8592061, 16971478). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265078). 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. 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 missense 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.
Natera, Inc. RCV001275768 SCV001461240 pathogenic Epidermolysis bullosa dystrophica inversa, autosomal recessive 2020-09-16 no assertion criteria provided clinical testing

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