ClinVar Genomic variation as it relates to human health

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.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16971478, 21448560, 31001817, 9326325, 20920254, 23947675, 28973459, 31589614, 29242947, 20184583, 29272047)

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. Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). This variant is present in population databases (rs768128088, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9326325, 20920254). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spanish ancestry (PMID: 9326325, 20920254). ClinVar contains an entry for this variant (Variation ID: 372345). For these reasons, this variant has been classified as Pathogenic.

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PM3 moderate

Variant summary: COL7A1 c.6527dupC (p.Gly2177TrpfsX113) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.8e-05 in 250676 control chromosomes. c.6527dupC has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive with the variant described as a founder mutation of Spanish origin (e.g. Cuadrado-Corrales_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 20920254). ClinVar contains an entry for this variant (Variation ID: 372345). Based on the evidence outlined above, the variant was classified as pathogenic.

The COL7A1 c.6527dupC variant is predicted to result in a frameshift and premature protein termination (p.Gly2177Trpfs*113). This variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with epidermolysis bullosa dystrophica (see for example - referred to as 6527insC in Hovnanian et al. 1997. PubMed ID: 9326325; Cuadrado-Corrales et al. 2010. PubMed ID: 20920254; Almaani et al. 2011. PubMed ID: 21448560). This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in COL7A1 are expected to be pathogenic. This variant is interpreted as pathogenic.