Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001233363 | SCV001405953 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-12-02 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 549439). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 2631 of the FBN1 protein (p.Cys2631Phe). |
| Centre of Medical Genetics, |
RCV000663993 | SCV002025465 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PVS2, PP4 |
| Gene |
RCV004760683 | SCV005373291 | likely pathogenic | not provided | 2024-04-04 | criteria provided, single submitter | clinical testing | Identified in patients with Marfan syndrome referred for genetic testing at GeneDx and in published literature (PMID: 35058154); Not observed at significant frequency in large population cohorts (gnomAD); Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 35058154) |
| Center for Medical Genetics Ghent, |
RCV000663993 | SCV000787377 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |