ClinVar

Description

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.