Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001380729 | SCV001578881 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-02-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an TGFBP 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: 11104663, 12203987, 16677079). In addition, missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in individuals with clinical features of Marfan syndrome (PMID: 21542060, Invitae). ClinVar contains an entry for this variant (Variation ID: 406267). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with glycine at codon 617 of the FBN1 protein (p.Cys617Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. |
| Centre of Medical Genetics, |
RCV000474956 | SCV002025518 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PVS2, PP4 |
| Center for Medical Genetics Ghent, |
RCV000474956 | SCV000786805 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |