Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002314323 | SCV000738816 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-08-24 | criteria provided, single submitter | clinical testing | The p.C1361Y pathogenic mutation (also known as c.4082G>A), located in coding exon 32 of the FBN1 gene, results from a G to A substitution at nucleotide position 4082. The cysteine at codon 1361 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #18 domain. This alteration has been previously reported in a patient with Marfan syndrome. Studies performed on patient fibroblasts showed fibrillin synthesis at 87% with fibrillin deposition at 10% of control, suggesting that this alteration reduced protein secretion (Schrijver I et al. Am J Hum Genet. 1999;65(4):1007-20; Yao Z et al. BMC Genomics. 2007;8:319). 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). In addition, internal structural analysis suggests this alteration is likely to disrupt a cysteine bridge in the EGF domain-like domain. Based on the available evidence, p.C1361Y is classified as a pathogenic mutation. |
| Centre of Medical Genetics, |
RCV000663692 | SCV002025297 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PVS2, PP4 |
| Invitae | RCV002531819 | SCV003442938 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-02-10 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 519726). For these reasons, this variant has been classified as 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. This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 10486319). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1361 of the FBN1 protein (p.Cys1361Tyr). |
| Center for Medical Genetics Ghent, |
RCV000663692 | SCV000787024 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |