Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000631936 | SCV000753039 | likely pathogenic | Marfan syndrome; Thoracic aortic aneurysm and aortic dissection | 2017-11-10 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with tyrosine at codon 2511 of the FBN1 protein (p.Cys2511Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with classical Marfan syndrome (PMID: 10533071). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, cysteine substitutions located in FBN1 EGF-like domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic. |
| Center for Medical Genetics Ghent, |
RCV000663961 | SCV000787338 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |