Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000559409 | SCV000627872 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-05-14 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 457182). 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. 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). 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 has not been reported in the literature in individuals affected with FBN1-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 958 of the FBN1 protein (p.Cys958Ser). This variant is not present in population databases (gnomAD no frequency). |