Submissions for variant NM_000094.4(COL7A1):c.4810G>C (p.Gly1604Arg)

dbSNP: rs1560234201

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778706	SCV000915059	uncertain significance	Epidermolysis bullosa dystrophica	2018-08-23	criteria provided, single submitter	clinical testing	The COL7A1 c.4810G>C (p.Gly1604Arg) missense variant has not been reported in the literature in association with dystrophic epidermolysis bullosa (DEB). However, another nucleotide change at the same position, c.4810G>A, which results in the same amino acid substitution, p.Gly1604Arg, has been reported in a compound heterozygous state with a frameshift variant in at least two individuals with DEB (Whittock et al. 1999; Wessagowit et al. 2004; Kim et al. 2018). Control data are unavailable for the p.Gly1604Arg variant. The variant also is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Consortium despite good coverage of the genomic region, suggesting it is rare. The evidence for this variant is limited. The p.Gly1604Arg variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for dystrophic epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003727821	SCV004529833	pathogenic	not provided	2024-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1604 of the COL7A1 protein (p.Gly1604Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive epidermolysis bullosa dystrophica (PMID: 10504458). ClinVar contains an entry for this variant (Variation ID: 631926). 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 with a positive predictive value of 95%. 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. This variant disrupts the p.Gly1604 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been observed in individuals with COL7A1-related conditions (PMID: 32484238), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.