ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4259G>A (p.Cys1420Tyr)

dbSNP: rs397515804
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035193 SCV000058835 likely pathogenic Marfan syndrome 2008-03-01 criteria provided, single submitter clinical testing
Invitae RCV000631934 SCV000753037 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-10-06 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 42354). This missense change has been observed in individuals with isolated ectopia lentis or Marfan syndrome (PMID: 22736615, 24793577). This variant is not present in population databases (ExAC no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.
Petrovsky National Research Centre 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.
Centre of Medical Genetics, University of Antwerp RCV000035193 SCV002025308 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS2, PP4
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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