Submissions for variant NM_000094.4(COL7A1):c.8246G>A (p.Gly2749Glu)

dbSNP: rs2107631988

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003660907	SCV004372411	likely pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	This variant disrupts the p.Gly2749 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8644729, 18450758, 29334134, 29473190). 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. ClinVar contains an entry for this variant (Variation ID: 1339157). 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 glutamic acid, which is acidic and polar, at codon 2749 of the COL7A1 protein (p.Gly2749Glu). 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.
PreventionGenetics, part of Exact Sciences	RCV003892879	SCV004711338	pathogenic	COL7A1-related disorder	2024-01-04	criteria provided, single submitter	clinical testing	The COL7A1 c.8246G>A variant is predicted to result in the amino acid substitution p.Gly2749Glu. This variant was reported in the homozygous state in 3 individuals with autosomal recessive dystrophic epidermolysis bullosa (Gupta et al. 2023. PubMed ID: 37556444). This variant has not been reported in a large population database, indicating this variant is rare. The amino acid residue p.Gly2749Glu is within the triple helical domain of the COL7A1 protein (amino acids 1254-2783); and glycine substitution within this domain affect the folding and secretion of type VII collagen. Pathogenic variants altering glycine residues have been reported in individuals with COL7A1-related disorders (Dang et al. 2008, PubMed ID: 18558993; Abu Sa'd et al. 2006. PubMed ID: 16439963; Almaani et al. 2011. PubMed ID: 21448560; Vahidnezhad et al. 2017. PubMed ID: 27899325). An alternate nucleotide change affecting the same amino acid (c.8245G>A; p.Gly2749Arg), has been reported in patients diagnosed with dystrophic epidermolysis bullosa (Gupta et al. 2023. PubMed ID: 37556444; Saeidian et al. 2018. PubMed ID: 29473190; Lucky et al. 2018. PubMed ID: 29334134). In summary, we interpret this variant as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823611	SCV002073182	uncertain significance	Recessive dystrophic epidermolysis bullosa		flagged submission	clinical testing	The missense variant p.G2749E in COL7A1 (NM_000094.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.G2749E variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. However, a pathogenic homozygous 8245G-A (p.G2749R) variant was reported at same codon in the COL7A1 gene in patients with autosomal recessive Epidermolysis Bullosa Dystrophica (Christiano et al, 1996). There is a moderate physicochemical difference between glycine and glutamic acid. The gene COL7A1 contains 58 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.G2749E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 2749 of COL7A1 is conserved in all mammalian species. The nucleotide c.8246 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.