ClinVar Miner

Submissions for variant NM_000094.4(COL7A1):c.5173G>A (p.Gly1725Arg)

gnomAD frequency: 0.00001  dbSNP: rs772195825
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521857 SCV000619040 pathogenic not provided 2021-05-07 criteria provided, single submitter clinical testing Occurs at a Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII 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; Not observed at a 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; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000521857 SCV001497159 uncertain significance not provided 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1725 of the COL7A1 protein (p.Gly1725Arg). This variant is present in population databases (rs772195825, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 450451). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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