Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003783680 | SCV004570977 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-04-16 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 85 of the FBN1 protein (p.Cys85Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 27724990; Invitae). 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 with a positive predictive value of 95%. 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. |
| ARUP Laboratories, |
RCV005230566 | SCV005877552 | pathogenic | not provided | 2024-06-10 | criteria provided, single submitter | clinical testing | The FBN1 c.254G>A; p.Cys85Tyr variant (ClinVar Variation ID: 2925586) is reported in the literature in an individual with a clinical diagnosis of Marfan syndrome (Zhurayev 2016). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant disrupts a conserved cystine residue in an EGF-like domain, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Based on available information, this variant is considered to be pathogenic. References: Zhurayev R et al. Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients. Genet Res (Camb). 2016 Oct 11;98:e13 PMID: 27724990 |