Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001377120 | SCV001574357 | pathogenic | not provided | 2024-03-01 | 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 2674 of the COL7A1 protein (p.Gly2674Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 8644729, 8900535; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1066186). 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 with a positive predictive value of 95%. 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. This variant disrupts the p.Gly2674 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been observed in individuals with COL7A1-related conditions (PMID: 10504458), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV005023119 | SCV005662028 | pathogenic | Recessive dystrophic epidermolysis bullosa; Pretibial dystrophic epidermolysis bullosa; Dominant dystrophic epidermolysis bullosa with absence of skin; Transient bullous dermolysis of the newborn; Epidermolysis bullosa pruriginosa; Nonsyndromic congenital nail disorder 8; Generalized dominant dystrophic epidermolysis bullosa | 2024-01-22 | criteria provided, single submitter | clinical testing |