Submissions for variant NM_000094.4(COL7A1):c.8156G>C (p.Gly2719Ala)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002651674	SCV003525220	pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2719 of the COL7A1 protein (p.Gly2719Ala). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive epidermolysis bullosa dystrophica (PMID: 16971478, 17425959, 21113014). 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: 2203354). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700978	SCV005203555	uncertain significance	not specified	2024-07-15	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.8156G>C (p.Gly2719Ala) results in a non-conservative amino acid change in 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 8e-06 in 250272 control chromosomes (gnomAD). c.8156G>C has been reported in the literature in individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (Dang_2007, Varki_2007, van den Akker_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Woodley_2021). The following publications have been ascertained in the context of this evaluation (PMID: 21448560, 21113014, 17425959, 34674926, 16500083, 16971478). ClinVar contains an entry for this variant (Variation ID: 2203354). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.