Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001225352 | SCV001397631 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2019-08-12 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with phenylalanine at codon 67 of the FBN1 protein (p.Cys67Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. 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. This variant disrupts the p.Cys67 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19839986, 27906200), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBN1-related conditions. This variant is not present in population databases (ExAC no frequency). |
| ARUP Laboratories, |
RCV001812259 | SCV001473756 | likely pathogenic | not provided | 2019-11-25 | criteria provided, single submitter | clinical testing | The FBN1 c.200G>T; p.Cys67Phe variant, to our knowledge, is not reported in the medical literature or gene specific databases. However, other variants at this codon and the adjacent cysteine codon (p.Cys67Arg, p.Cys67Ser, p.Cys67Tyr, p.Cys68Phe, p.Cys68Ser, p.Cys68Trp) have been reported in association with Marfan syndrome (Hung 2009, Groth 2017). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a cysteine residue that is part of a known 4-cysteine motif and the p.Cys67Phe variant is predicted to disrupt disulfide bridge formation (Yadin 2013, Groth 2017). Based on available information, this variant is considered to be, likely pathogenic. |