ClinVar Miner

Submissions for variant NM_000094.4(COL7A1):c.8165G>T (p.Gly2722Val)

dbSNP: rs759949767
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biomedical Innovation Departament, CIEMAT RCV001352715 SCV001547391 pathogenic Epidermolysis bullosa dystrophica 2018-11-23 criteria provided, single submitter research
PreventionGenetics, part of Exact Sciences RCV003405591 SCV004108112 pathogenic COL7A1-related disorder 2022-12-21 criteria provided, single submitter clinical testing The COL7A1 c.8165G>T variant is predicted to result in the amino acid substitution p.Gly2722Val. This variant has been reported in three patients with dystrophic epidermolysis bullosa, two of which were compound heterozygous for a second pathogenic or potentially pathogenic variant and the third patient in which a second pathogenic variant was not identified (Saeidian et al 2018. PubMed ID: 29427316; Table S1, Cuadrado-Corraleset al. 2010. PubMed ID: 20920254). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. The amino acid residue p.Gly2722 is within the triple helical domain of the COL7A1 protein. Glycine substitutions within this domain affect the folding and secretion of type VII collagen, and pathogenic variants altering glycine residues have been reported in individuals with COL7A1-related disorders (Dang et al. 2008, PubMed ID: 18558993; Abu Sa'd et al. 2006. PubMed ID: 16439963; Almaani et al. 2011. PubMed ID: 21448560; Vahidnezhad et al. 2017. PubMed ID: 27899325). This variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003727988 SCV004540546 pathogenic not provided 2022-12-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2722 of the COL7A1 protein (p.Gly2722Val). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 1047950). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 29427316). This variant is not present in population databases (gnomAD no frequency).

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