Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003781410 | SCV004573394 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 377 of the FBN1 protein (p.Cys377Gly). 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 disrupts the p.Cys377 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28855619, 33436942), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with Marfan syndrome (PMID: 29848614). This variant is not present in population databases (gnomAD no frequency). |
| Ambry Genetics | RCV004621901 | SCV005113182 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-05-01 | criteria provided, single submitter | clinical testing | The p.C377G variant (also known as c.1129T>G), located in coding exon 9 of the FBN1 gene, results from a T to G substitution at nucleotide position 1129. The cysteine at codon 377 is replaced by glycine, an amino acid with highly dissimilar properties. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the TB domain 1 (Ambry internal data). Another variant at the same codon, p.C377R (c.1129T>C), has been reported in an individual with a clinical diagnosis of Marfan syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |