Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002221419 | SCV002498686 | likely pathogenic | Epidermolysis bullosa dystrophica | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change in COL7A1 is predicted to replace glycine with valine at codon 2114, p.(Gly2114Val). The glycine residue is moderately conserved (100 vertebrates, UCSC), and alters a critical glycine residue in a collagen triple helix repeat (Gly-X-Y) in the collagenous domain. There is a large physicochemical difference between glycine and valine. This variant is present in a single individual in gnomAD v3.1 in the South Asian population (1/4,824 alleles). To our knowledge, this variant has not been reported in the literature in any individuals with COL7A1-related disorders. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Another missense variant c.6341G>A p.(Gly2114Asp) in the same codon has been classified as likely pathogenic for recessive dystrophic epidermolysis bullosa (PMID: 20920254, 31090061). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM5, PM2_Supporting, PP3. |
| Labcorp Genetics |
RCV003107968 | SCV003782851 | likely pathogenic | not provided | 2023-07-08 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly2114 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31090061). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 1676257). This variant has not been reported in the literature in individuals affected with COL7A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2114 of the COL7A1 protein (p.Gly2114Val). |