Submissions for variant NM_000094.4(COL7A1):c.8324G>A (p.Gly2775Asp)

dbSNP: rs773146110

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003675713	SCV004393685	likely pathogenic	not provided	2023-02-10	criteria provided, single submitter	clinical testing	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 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.Gly2775 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9740253, 10504458, 11781296, 20555349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2775 of the COL7A1 protein (p.Gly2775Asp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005407206	SCV006074376	likely pathogenic	Epidermolysis bullosa dystrophica	2025-04-24	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.8324G>A (p.Gly2775Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat region (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 1607054 control chromosomes in the gnomAD database (v4.1 dataset). To our knowledge, no occurrence of c.8324G>A in individuals affected with Dystrophic Epidermolysis Bullosa and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.8323G>A, p.Gly2775Asp), supporting the critical relevance of codon 2775 to COL7A1 protein function. ClinVar contains an entry for this variant (Variation ID: 2798318). Based on the evidence outlined above, the variant was classified as likely pathogenic.