ClinVar Genomic variation as it relates to human health

The missense variant p.G2043R in COL7A1 (NM_000094.4) is the most common recurrent variant in the autosomal dominant dystrophic epidermolysis bullosa (Christiano et al, Nishie et al,Vahidnezhad et al). It has been reported to ClinVar as Pathogenic.The p.G2043R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.G2043R missense variant is predicted to be damaging by both SIFT and PolyPhen2.The glycine residue at codon 2043 of COL7A1 is conserved in all mammalian species. The nucleotide c.6127 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

For these reasons, this variant has been classified as Pathogenic. 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. 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: 17438). This missense change has been observed in individual(s) with autosomal dominant dystrophic epidermolysis bullosa (PMID: 7861014). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2043 of the COL7A1 protein (p.Gly2043Arg).

Variant summary: COL7A1 c.6127G>A (p.Gly2043Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of 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 243,072 control chromosomes (gnomAD). c.6127G>A has been reported in the literature in multiple individuals affected with Dominant Dystrophic Epidermolysis Bullosa (eg. Christiano_1995, Nishie_2014, Vahidnezhad_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in accumulation of collagen VII in the cytoplasm and increased susceptibility to enzymatic degradation (Nishie_2014). One other clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

One of the most common recurrent pathogenic variants identified in DDEB patients across all ethnic backgrounds (Nanda et al., 2018; Yenamandra et al., 2018; Chen et al., 2020); Published functional studies demonstrate a damaging effect, as G2043R induces intracytoplasmic accumulation of pro-C7, which hampers secretion of C7 in a dominant-negative fashion (Nishie et al., 2014); Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24794830, 7861014, 28830826, 21448560, 9892921, 11260189, 9856843, 10951471, 32946877, 32506551, 31604626, 30011071, 29963685, 32484238, 9412818, 33274474)

The COL7A1 c.6127G>A variant is predicted to result in the amino acid substitution p.Gly2043Arg. This variant has been previously reported in the heterozygous state in affected members of a family with autosomal dominant dystrophic epidermolysis bullosa (Christiano et al. 1995. PubMed ID: 7861014). It has also been reported as a recurrent de novo or inherited variant in many individuals with autosomal dominant dystrophic epidermolysis bullosa (Mellerio et al. 1998. PubMed ID: 9892921; Rouan et al. 1998. PubMed ID: 9856843; Wessagowit et al. 2001. PubMed ID: 11260189; Table S1, Almaani et al. 2011. PubMed ID: 21448560; Nishie et al. 2014. PubMed ID: 24794830; Supplementary Table S1, Vahidnezhad et al. 2017. PubMed ID: 28830826; Yenamandra et al. 2018. PubMed ID: 29963685; Nanda et al. 2018. PubMed ID: 30011071; Table S3, Chen et al. 2020. PubMed ID: 32484238). Furthermore, this variant resides in exon 73 and results in a glycine residue substitution. Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) are predominant in autosomal dominant dystrophic epidermolysis bullosa (DDEB; https://www.ncbi.nlm.nih.gov/books/NBK1304/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.