ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.7344G>A (p.Val2448=) (rs201728948)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414113 SCV000490507 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The c.7344 G>A pathogenic variant in the COL7A1 gene has been reported previously in multiple patients with dystrophic epidermolysis bullosa (Gardella et al. 1996; Gardella et al. 2002). In silico analysis predicts this variant damages the natural splice donor site of intron 95. Analysis of RNA transcripts derived from a patient indicated that c.7344 G>A produces both some normal and an abnormal mRNA that is missing the last 7 nucleotides of exon 95 as a consequence of the usage of a cryptic splice donor site located 7bp upstream of the natural donor site. The c.7344 G>A is observed in 8/257556 (0.0031%) alleles in large population cohorts (Lek et al., 2016). In addition, numerous other splicing variants have been reported in the Human Gene Mutation Database in association with DEB (Stenson et al., 2014). Therefore, we interpret c.7344 G>A as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763112 SCV000893654 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 RCV000414113 SCV000964501 pathogenic not provided 2018-09-17 criteria provided, single submitter clinical testing This sequence change affects codon 2448 of the COL7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL7A1 protein. This variant also falls at the last nucleotide of exon 95 of the COL7A1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201728948, ExAC 0.008%). This variant has been observed in individuals affected with epidermolysis bullosa dystrophica (PMID: 10504458, 12485454, 16271705), and has been shown on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (PMID: 8755915). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 372349). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant causes abnormal splicing (PMID: 8755915). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018980 SCV000039267 pathogenic Epidermolysis bullosa dystrophica, autosomal recessive, localisata variant 2006-10-01 no assertion criteria provided literature only
OMIM RCV000018981 SCV000039268 pathogenic Epidermolysis bullosa pruriginosa, autosomal recessive 2006-10-01 no assertion criteria provided literature only
Natera, Inc. RCV001275769 SCV001461241 pathogenic Epidermolysis bullosa dystrophica inversa, autosomal recessive 2020-09-16 no assertion criteria provided clinical testing

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