ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4539C>G (p.Cys1513Trp) (rs1555397203)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770666 SCV000902125 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2016-05-11 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000663737 SCV000787076 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Invitae RCV000550970 SCV000627919 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-06-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 1513 of the FBN1 protein (p.Cys1513Trp). 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 (ExAC no frequency). This variant has been reported in individuals affected with Marfan syndrome (PMID: 16476890, 17627385, 19293843). This variant generates a cysteine residue in 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: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.

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