ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4293C>G (p.Cys1431Trp) (rs112375043)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000663712 SCV000787048 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Invitae RCV000542755 SCV000627908 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-03-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 1431 of the FBN1 protein (p.Cys1431Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (rs112375043, ExAC no frequency). This variant has been observed in an individual who fulfilled the Ghent nosology, findings that are highly specific for Marfan syndrome (PMID: 21542060). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.

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