Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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, |
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, |
RCV000035193 | SCV002025308 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PVS2, PP4 |
Center for Medical Genetics Ghent, |
RCV000035193 | SCV000787038 | pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |