ClinVar Miner

Submissions for variant NM_000494.4(COL17A1):c.2336-2A>G (rs1478395810)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778270 SCV000914443 likely pathogenic Adult junctional epidermolysis bullosa 2018-10-16 criteria provided, single submitter clinical testing The COL17A1 gene is one of four genes in which variants are known to cause junctional epidermolysis bullosa. The COL17A1 c.2336-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.2336-2A>G variant has been reported in two studies in which it is found in a homozygous state in two individuals, one with generalized atrophic benign epidermolysis bullosa and one with junctional epidermolysis bullosa, and in a heterozygous state in six unaffected relatives (Chavanas et al. 1997; Väisänen et al. 2005). The c.2336-2A>G variant was absent from 100 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. Western blot analysis confirmed the absence of COL17A1 protein in keratinocytes from one of the probands homozygous for the variant (Chavanas et al. 1997). Expression analysis in COS-7 cells demonstrated structural variance in the NC15 domain while retaining thermal stability (Väisänen et al. 2005). Expression in COS-7 cells also demonstrated the c.2336-2A>G variant did not affect N-glycosylation, localization at the plasma membrane, or migration of collagen XVII (Huilaja et al. 2009). The variant is in a highly conserved consensus splice acceptor site. Direct sequencing in cultured proband keratinocytes found the c.2336-2A>G causes an in-frame deletion that results in the skipping of exon 32 in the COL17A1 gene (Chavanas et al. 1997). Based on evidence, the c.2336-2A>G variant is classified as likely pathogenic for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000778270 SCV000039507 pathogenic Adult junctional epidermolysis bullosa 1997-07-01 no assertion criteria provided literature only

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