ClinVar Genomic variation as it relates to human health

The NM_000094.3(COL7A1):c.1732C>T heterozygous nonsense variant was identified in exon 13 of COL7A1. This nonsense variant creates a stop codon at amino acid position 578, NP_000085.1(COL7A1):p.(Arg578*). This is predicted to result in loss of protein function either through truncation (~75% of the protein, including multiple triple helix repeats) or nonsense-mediated decay. This variant is present in the gnomAD population database at a frequency of 0.004%. It has been previously reported in multiple families with recessive dystrophic epidermolysis bullosa in homozygous or compound heterozygous state (Dunnill et al., (1994), Whittock et al., (1999) and Kern et al., (2006)). In addition, other truncating variants downstream of c.1732C>T in the COL7A1 gene have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information and in association with the NM_000094.3(COL7A1):c.3265C>T nonsense variant, this variant has been classified as PATHOGENIC.

The COL7A1 c.1732C>T (p.Arg578Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, The p.Arg578Ter variant has been found in at least 21 individuals with dystrophic epidermolysis bullosa, including in four in a homozygous state, in at least 15 in a compound heterozygous state, and in at least two in a heterozygous state (Dunnill et al. 1994; Hovnanian et al. 1997; Mellerio et al. 1997; Whittock et al. 1999; Almaani et al. 2010; Nagy et al. 2011; Petrof et al. 2013; Takeichi et al. 2015; Serafi et al. 2015; Georgiadis et al. 2016). Three of the studies demonstrated that the p.Arg578Ter variant segregated with disease (Dunnill et al. 1994; Mellerio et al. 1997; Serafi et al. 2015). The p.Arg578Ter variant was absent from 180 control chromosomes and is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. The p.Arg578Ter variant is predicted to result in premature termination and the loss of approximately 80% of the protein. Due to the potential impact of stop-gained variants and available evidence, the p.Arg578Ter variant is classified as pathogenic for dystrophic epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Nonsense 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: 21448560, 28549954, 25525159, 26102279, 7833933, 10504458, 14727126, 28168442, 20357813, 28691931, 29625052, 26689913, 33274474)

This sequence change creates a premature translational stop signal (p.Arg578*) 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 (rs144023803, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 17425959, 26102279). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372330). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The stop gained c.1732C>T p.Arg578Ter variant in COL7A1 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Epidermolysis bullosa dystrophica Whittock et al., 1999; Alamani et al., 2010; Serafi et al., 2015. The p.Arg578Ter variant has been reported to segregated with disease Serafi et al., 2015. The p.Arg578Ter variant is reported with allele frequency of 0.03% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The nucleotide change c.1732C>T in COL7A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal p.Arg578Ter in the COL7A1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in COL7A1 gene have been previously reported to be pathogenic Varki et al., 2007. For these reasons, this variant has been classified as Pathogenic.

ACMG categories: PVS1,PM2,PP3,PP5

The COL7A1 c.1732C>T variant is predicted to result in premature protein termination (p.Arg578*). This variant has been previously reported in the homozygous or compound heterozygous state in individuals with epidermolysis bullosa dystrophica (Dang et al. 2007. PubMed ID: 17425959; Table SII, Almaani et al. 2011. PubMed ID: 21448560; Serafi et al. 2015. PubMed ID: 26102279; Table S6, Rossi et al. 2021. PubMed ID: 33274474). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in COL7A1 are expected to be pathogenic. This variant is interpreted as pathogenic.