ClinVar Miner

Submissions for variant NM_000094.4(COL7A1):c.6760G>A (p.Gly2254Arg)

dbSNP: rs2107659888
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002244235 SCV002512629 likely pathogenic Recessive dystrophic epidermolysis bullosa; Generalized dominant dystrophic epidermolysis bullosa 2022-01-24 criteria provided, single submitter clinical testing ACMG classification criteria: PM1 moderate, PM2 moderate, PM5, PP3 supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV005095799 SCV005734876 pathogenic not provided 2025-01-13 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 2254 of the COL7A1 protein (p.Gly2254Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive epidermolysis bullosa dystrophica (internal data). 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: 1683714). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. For these reasons, this variant has been classified as Pathogenic.

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