Submissions for variant NM_000094.4(COL7A1):c.8065G>A (p.Gly2689Arg)

gnomAD frequency: 0.00002  dbSNP: rs748940147

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001529857	SCV002118556	pathogenic	not provided	2024-01-08	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 2689 of the COL7A1 protein (p.Gly2689Arg). This variant is present in population databases (rs748940147, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive epidermolysis bullosa dystrophica (PMID: 16484981, 21113014, 32484238). 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: 1175072). 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. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545825	SCV004046319	pathogenic	COL7A1-related disorder		criteria provided, single submitter	clinical testing	The p.Gly2689Arg affects a moderately conserved amino acid glycine in C-terminal portion of the triple helical domain of collagen VII and is predicted to have a deleterious effect on protein function by PolyPhen-2 and MutationTaster, whereas SIFT predicts the change as tolerated. This variant has been previously reported as a compound heterozygous change or together with another COL7A1 alteration, phase unknown, in patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB) (PMID: 21448560; 32484238; 16484981). A different nucleotide change causing the same amino acid alteration, c.8065G>C (p.Gly2689Arg), has been previously reported in one individual with RDEB (PMID: 21113014). Experimental studies using Procollagen VII extracted from keratinocytes of affected patients showed that the p.Gly2689Arg reduced stability of the triple helix of collagen VII (PMID: 16484981). The c.8065G>A (p.Gly2689Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/251228) and thus is presumed to be rare. Based on the available evidence, the c.8065G>A (p.Gly2689Arg) variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529857	SCV001744052	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529857	SCV001953378	pathogenic	not provided		no assertion criteria provided	clinical testing