ClinVar Genomic variation as it relates to human health

Published functional studies suggest a damaging effect due to aberrant formation of homo-trimers, decreased thermal stability, and decreased induction of keratinocyte migration as compared to wildtype (Woodley et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located at the Y position in a Gly-X-Y repeat within triple-helical region; This variant is associated with the following publications: (PMID: 26707537, 20920254, 20555349, 20598510, 20184583, 12485454, 21448560, 31001817, 22266148, 31589614, 33274474, 34674926)

Variant summary: COL7A1 c.7864C>T (p.Arg2622Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251164 control chromosomes (i.e., 5 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7864C>T has been reported in the literature in multiple individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Gardella_2002, Escamez_2010, Jerabkova_2010, Almaani_2011, Wertheim-Tysarowska_2012, Mariath_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21448560, 20184583, 12485454, 20598510, 31001817, 22266148). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 3) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2622 of the COL7A1 protein (p.Arg2622Trp). This variant is present in population databases (rs139318843, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 12485454, 20184583, 21448560, 22266148). 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: 449005). 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. For these reasons, this variant has been classified as Pathogenic.

The COL7A1 c.7864C>T variant is predicted to result in the amino acid substitution p.Arg2622Trp. This variant has been reported with a second COL7A1 variant in individuals with autosomal recessive epidermolysis bullosa dystrophica (see for example, Gardella et al. 2002. PubMed ID: 12485454; Escámez et al. 2010. PubMed ID: 20184583; Almaani et al. 2011. PubMed ID: 21448560). In vitro functional studies suggest this variant impacts protein function (Woodley et al. 2021. PubMed ID: 34674926). An alternative nucleotide substitution affecting the same amino acid (p.Arg2622Gln) has also been reported in an individual with epidermolysis bullosa dystrophica (Appendix I, Varki et al. 2007. PubMed ID: 16971478). The p.Arg2622Trp variant is reported in 0.016% of alleles in individuals of African descent in a large population database. This variant is interpreted as pathogenic.