ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4259G>A (p.Cys1420Tyr) (rs397515804)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035193 SCV000058835 likely pathogenic Marfan syndrome 2008-03-01 criteria provided, single submitter clinical testing
Invitae RCV000631934 SCV000753037 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1420 of the FBN1 protein (p.Cys1420Tyr). 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 isolated ectopia lentis or Marfan syndrome (PMID: 22736615, 24793577). ClinVar contains an entry for this variant (Variation ID: 42354). 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). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000035193 SCV000965599 pathogenic Marfan syndrome 2019-08-01 criteria provided, single submitter clinical testing The p.Cys1420Tyr variant was reported in individuals with MFS (PMID: 22736615, 24793577) and is absent from large population studies. The variants has entry in dbSNP and ClinVar (rs397515804, Variation ID:42354). The Cys1420 residue is forming a disulfide bonds 1408-1420 in the cbEGF-like domain. Cysteine substitutions in such domains are a well known mutations with pathogenic consequences (PMID: 1301946, 15161917). In addition, computational results of Provean, PolyPhen2, MutationTaster show damaging effect.
Center for Medical Genetics Ghent,University of Ghent RCV000035193 SCV000787038 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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