Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001389171 | SCV001590439 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-08-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 1075547). This missense change has been observed in individuals with Marfan syndrome (PMID: 10189222; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1818 of the FBN1 protein (p.Cys1818Tyr). |
| Laboratory for Molecular Medicine, |
RCV004017833 | SCV004848460 | likely pathogenic | Marfan syndrome | 2020-08-24 | criteria provided, single submitter | clinical testing | The p.Cys1818Tyr variant in FBN1 has been identified in 1 individual with Marfan syndrome (Perez 1998 PubMed: 10189222) and was absent from large population studies. Two additional variants involving this codon (p.Cys1818Gly and p.Cys1818Ser) have been identified in individuals with Marfan syndrome (Yoo 2010 PMID: 19863550; Seo 2018 PMID: 29768367). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM1; PM2; PM5_Supporting; PS4_Supporting; PP3. |