Submissions for variant NM_000094.4(COL7A1):c.6101G>C (p.Gly2034Ala)

dbSNP: rs1057520530

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000440486	SCV000515904	pathogenic	not provided	2015-03-30	criteria provided, single submitter	clinical testing	The G2034A variant in the COL7A1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The G2034A substitution was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G2034Avariant is a conservative amino acid substitution, however it is found in the triple helical domain of thecollagen molecule where the canonical Gly-X-Y motif is highly conserved and necessary for the properwinding of the collagen triple helix. Although in silico analysis is inconsistent in its predictions as to whetheror not the variant is damaging to the protein structure/function, Glycine substitutions in thisregion of the protein are known to be pathogenic. Numerous missense variants at the same residue or innearby residues (G2034R, W, V, E and G2028R, G2031S, G2037R) have been reported in the HumanGene Mutation Database in association with dystrophic epidermolysis bullosa (Stenson et al., 2014),supporting the functional importance of this region of the protein. Additionally, G2034A is found in exon 73of the COL7A1 gene where Glycine substitution variants cluster. We interpret G2034A as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000440486	SCV003460746	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 379224). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 29473190). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2034 of the COL7A1 protein (p.Gly2034Ala).