ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2306G>A (p.Cys769Tyr) (rs794728190)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000663528 SCV000786837 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000605926 SCV000731213 likely pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Invitae RCV000631933 SCV000753036 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-01-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 769 of the FBN1 protein (p.Cys769Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Marfan syndrome (PMID: 19293843, 20564469). 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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