Submissions for variant NM_000094.4(COL7A1):c.7723G>A (p.Gly2575Arg)

gnomAD frequency: 0.00001  dbSNP: rs760891216

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255334	SCV000321513	pathogenic	not provided	2016-02-27	criteria provided, single submitter	clinical testing	The Gly2575Arg pathogenic variant in the COL7A1 gene has been reported previously (Shimizu et al 1996, Pfendner et al 2003, Kern et al., 2006, Saito et al., 2008). The Gly2575Arg variant is reported to affected disulfide bonding between colVII monomers to form the trimer mature col7 fibers Woodley et al., 2008) and also affects the formation of heterotypic trimers more than homotypic ones (Brittingham et al 2005). The Gly2575Arg variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Gly2575Arg variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Numerous Glycine substitution variants throughout the COL7A1 gene and missense variants in nearby residues (R2580C) have been reported in the Human Gene Mutation Database in association with DEB (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Gly2575Arg as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255334	SCV001589398	pathogenic	not provided	2024-11-17	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 2575 of the COL7A1 protein (p.Gly2575Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 8592061, 16971478). 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: 265078). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL7A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COL7A1 function (PMID: 18450758). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823128	SCV002073313	pathogenic	Recessive dystrophic epidermolysis bullosa		criteria provided, single submitter	clinical testing	The missense variant p.G2575R in COL7A1 (NM_000094.4) has been previously reported in affected patients (Kern et al, 2006).Functional studies suggest a damaging effect (Brittingham et al 2005). The variant has been submitted to ClinVar as Pathogenic. The p.G2575R variant is observed in 3/80,562 (0.0037%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G2575R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 2575 of COL7A1 is conserved in all mammalian species. The nucleotide c.7723 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004529454	SCV003934235	pathogenic	COL7A1-related disorder	2023-05-02	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.7723G>A (p.Gly2575Arg) results in a non-conservative amino acid change located in the first fibronectin type III repeat domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 191218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7723G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Shimizu_1996, Hovnanian_1997, Kern_2006, Almaani_2011, Matsumura_2018, Chiaverini_2014). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, finding that the variant alters intermolecular interactions, thus affecting type VII collagen homotrimer processing and assembly (e.g., Brittingham_2005, Woodley_2008, Matsumura_2018). The following publications have been ascertained in the context of this evaluation (PMID: 21448560, 15509587, 24252097, 9326325, 16484981, 29229433, 8592061, 18450758). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001275768	SCV001461240	pathogenic	Epidermolysis bullosa dystrophica inversa, autosomal recessive	2020-09-16	no assertion criteria provided	clinical testing