Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003046156 | SCV003324034 | uncertain significance | not provided | 2022-03-14 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Gly2221 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been observed in individuals with COL7A1-related conditions (PMID: 20184583, 21448560), which suggests that this may be a clinically significant amino acid residue. 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. This variant has not been reported in the literature in individuals affected with COL7A1-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2221 of the COL7A1 protein (p.Gly2221Glu). |
| Gene |
RCV003046156 | SCV003929849 | pathogenic | not provided | 2023-03-06 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; 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 (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function |