ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5930G>A (p.Cys1977Tyr) (rs1555395663)

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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 RCV000663836 SCV000787193 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Invitae RCV000631921 SCV000753024 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-01-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1977 of the FBN1 protein (p.Cys1977Tyr). 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 individuals affected with Marfan syndrome (PMID: 9399842, 15241795). Experimental studies indicate that this missense change causes EGF-l intradomain misfolding (PMID: 15371449). 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). Two additional missense substitutions at this codon (p.Cys1977Arg, p.Cys1977Trp) have been reported in individuals affected with Marfan syndrome (PMID: 12161601, 18435798). For these reasons, this variant has been classified as Pathogenic.

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