Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Centre of Medical Genetics, |
RCV000663538 | SCV002025536 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PVS2, PP4 |
| Ambry Genetics | RCV002442388 | SCV002735306 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2017-04-05 | criteria provided, single submitter | clinical testing | The p.C811Y variant (also known as c.2432G>A), located in coding exon 20 of the FBN1 gene, results from a G to A substitution at nucleotide position 2432. The cysteine at codon 811 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #09 domain. 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). This alteration was first reported in one individual with a diagnosis of Marfan syndrome based on Ghent criteria (Baetens M et al. Hum. Mutat., 2011 Sep;32:1053-62). It was also reported in a 13 year old male with bilateral iridodenesis, but was absent from his unaffected parents (Jaradat SA et al. Int J Clin Exp Med, 2015 Oct;8:18786-92). 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. |
| Invitae | RCV003767930 | SCV004570969 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-02-23 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 811 of the FBN1 protein (p.Cys811Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 21542060, 34550612). ClinVar contains an entry for this variant (Variation ID: 549081). 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). For these reasons, this variant has been classified as Pathogenic. |
| Center for Medical Genetics Ghent, |
RCV000663538 | SCV000786849 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |