ClinVar Miner

Submissions for variant NM_000094.4(COL7A1):c.6527dupC (rs768128088)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413123 SCV000490503 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The c.6527dupC variant in the COL7A1 gene has been reported previously in association with autosomal recessive dystrophic epidermolysis bullosa (RDEB), and is a common recurrent variant in individuals of Spanish descent (Hovnanian et al. 1997; Varki et al. 2007; Chamorro et al 2013; Escamez et al., 2010; Cuadrado-Corrales et al., 2010). This variant causes a frameshift starting with codon Glycine 2177, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 113 of the new reading frame, denoted p.Gly2177TrpfsX113. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.6527dupC variant is observed in 14/33,572 alleles (0.04%) from individuals of Latino background in large population cohorts (Lek et al., 2016), consistent with the high prevalence of the c.6527dupC variant in Spanish patients with dystrophic epidermolysis bullosa (Escamez et al., 2010; Cuadrado-Corrales et al., 2010). We interpret c.6527dupC as a pathogenic variant.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454227 SCV000538019 pathogenic Recessive dystrophic epidermolysis bullosa 2015-12-04 criteria provided, single submitter clinical testing The c.6527dupC (p.Gly2177Trpfs*113) frameshift variant in the COL7A1 gene has been previously reported in at least 27 affected individuals with autosomal recessive Dystrophic Epidermolysis Bullosa and is predicted to prematurely truncate the protein. Affected individuals have harbored this frameshift variant in trans with a splice-site variant (7930-1G>C) and several missense variants (G2587D, G2434R, G2366D, G1383R) (Hovnanian et al., 1997; Cuadrado-Corrales et al., 2010; Kern et al. 2006). Loss of functions variants have been described in the COL7A1 gene in several affected individuals (OMIM#: 120120) and are, therefore, a common mechanism of disease. Functional studies have shown gene and protein expression are not detectable when this variant is present (Hovnanian et al., 1997; Cuadrado-Corrales et al., 2010).This c.6527dupC variant is absent from two control population databases (Exome Sequencing Project [ESP] and 1000 Genomes) and present at a low frequency in a third control population database (ExAC = 0.044%). In silico algorithms predict the nucleotide position where this variant occurs is conserved (GERP = 4.53). Therefore, this collective evidence supports the classification of the c.6527dupC (p.Gly2177Trpfs*113) as a recessive Pathogenic variant for Dystrophic Epidermolysis Bullosa.
Invitae RCV000413123 SCV000942042 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly2177Trpfs*113) in the COL7A1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768128088, ExAC 0.04%). This variant has been observed in several individuals affected with dystrophic epidermolysis bullosa and is considered a founder mutation in the Spanish population (PMID: 20920254, 9326325). ClinVar contains an entry for this variant (Variation ID: 372345). Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001266180 SCV001444352 pathogenic Inborn genetic diseases 2019-03-07 criteria provided, single submitter clinical testing
Biomedical Innovation Departament, CIEMAT RCV001352936 SCV001547559 pathogenic Dystrophic epidermolysis bullosa 2019-02-25 criteria provided, single submitter research
Natera, Inc. RCV001272346 SCV001454257 pathogenic Epidermolysis bullosa dystrophica inversa, autosomal recessive 2020-09-16 no assertion criteria provided clinical testing

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