Submissions for variant NM_000094.4(COL7A1):c.8786G>A (p.Cys2929Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005088617	SCV005726622	uncertain significance	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.8786G>A (p.Cys2929Tyr) 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 was absent in 250264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8786G>A has been reported in the literature in a compound heterozygous individual affected with Dystrophic Epidermolysis Bullosa, Recessive (Kopekov_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26707537). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005105429	SCV005834410	pathogenic	not provided	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2929 of the COL7A1 protein (p.Cys2929Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 26707537). 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 95%. This variant disrupts the p.Cys2929 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.