ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.1637-1G>A (rs886058642)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000271699 SCV000445138 likely pathogenic Dystrophic epidermolysis bullosa 2017-04-27 criteria provided, single submitter clinical testing The COL7A1 c.1637-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1637-1G>A variant has been reported in three individuals with dystrophic epidermolysis bullosa, including in one in a homozygous state, in one in a compound heterozygous state, and in at least one individual of unknown zygosity (Whittock et al. 1999; Pfendner et al. 2003; Varki et al. 2007). Control data are unavailable for the c.1637-1G>A variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. RT-PCR analysis demonstrated that the variant results in truncation of the COL7A1 protein (Whittock et al. 1999). Based on the evidence and the potential impact of splice acceptor variants, the c.1637-1G>A variant is classified as likely pathogenic for dystrophic epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000414605 SCV000490482 pathogenic not provided 2015-04-29 criteria provided, single submitter clinical testing The c.1637 - 1G>A pathogenic variant in the COL7A1 gene has been reported previously in association with DEB (Whittock et al., 1999). This splice site variant destroys the canonical splice acceptor site in intron 12. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1637-1G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1637-1G>A as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763515 SCV000894319 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
Invitae RCV000414605 SCV001207524 pathogenic not provided 2019-12-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the COL7A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another COL7A1 variant in individual(s) with epidermolysis bullosa (PMID: 10504458, 12813757). ClinVar contains an entry for this variant (Variation ID: 345869). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). For these reasons, this variant has been classified as Pathogenic.

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