ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.1732C>T (p.Arg578Ter) (rs144023803)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413975 SCV000490481 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing The R578X variant in the COL7A1 gene has been reported previously in association with dystrophic epidermolysis bullosa (DEB) either in the homozygous state or in combination with another COL7A1 variant (Dunnill et al., 1994; Whittock et al., 1999; Varki et al., 2006; Almaani et al., 2010; Serafi et al., 2015; Woodley et al., 2017). R578X has also been reported in the heterozygous state in at least two individuals reported to have recessive DEB in whom a second variant was not identified (Whittock et al., 1999). The R578X variant is observed in 3/33,578 (0.009%) alleles from individuals of Latino background, and in 10/246,122 (0.004%) total alleles in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret R578X as a pathogenic variant, with an autosomal recessive inheritance pattern.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000578166 SCV000680020 pathogenic Recessive dystrophic epidermolysis bullosa 2017-08-30 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000763514 SCV000894318 pathogenic Recessive dystrophic epidermolysis bullosa; Pretibial epidermolysis bullosa; Dominant dystrophic epidermolysis bullosa with absence of skin; Transient bullous dermolysis of the newborn; Epidermolysis bullosa pruriginosa; Nail disorder, nonsyndromic congenital, 8; Generalized dominant dystrophic epidermolysis bullosa 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779414 SCV000916027 pathogenic Dystrophic epidermolysis bullosa 2018-08-22 criteria provided, single submitter clinical testing 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.
Invitae RCV000413975 SCV001230729 pathogenic not provided 2020-07-03 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs144023803, ExAC 0.008%). This variant has been observed to segregate with autosomal recessive dystrophic epidermolysis bullosa in multiple families (PMID: 26102279, 17425959). ClinVar contains an entry for this variant (Variation ID: 372330). Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000578166 SCV001456298 pathogenic Recessive dystrophic epidermolysis bullosa 2020-09-16 no assertion criteria provided clinical testing

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