Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002424568 | SCV002743155 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-04-21 | criteria provided, single submitter | clinical testing | The p.C862Y pathogenic mutation (also known as c.2585G>A), located in coding exon 21 of the FBN1 gene, results from a G to A substitution at nucleotide position 2585. The cysteine at codon 862 is replaced by tyrosine, 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). This variant has been detected in individuals with Marfan syndrome (MFS) (Madar L et al. J Biotechnol, 2019 Aug;301:105-111; Ambry internal data). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the hybrid motif #02 region. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV002530608 | SCV003442970 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-07-03 | 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 862 of the FBN1 protein (p.Cys862Tyr). 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. ClinVar contains an entry for this variant (Variation ID: 549097). This missense change has been observed in individuals with Marfan syndrome (PMID: 24078565, 31163209). This variant is not present in population databases (gnomAD no frequency). |
| Center for Medical Genetics Ghent, |
RCV000663558 | SCV000786869 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing | |
| Department of Laboratory Medicine and Genetics, |
RCV000663558 | SCV005684870 | pathogenic | Marfan syndrome | 2025-01-02 | no assertion criteria provided | clinical testing | The NM_000138.5:c.2585G>A is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (REVEL). This variant is located in functional domains and a different missense variant at the same residue is determined to be pathogenic (c.2584T>C, p.Cys862Arg; c.2585G>T, p.Cys862Phe; c.2584T>A, p.Cys862Ser). This variant was found in a patient with Marfan syndrome meeting revised Ghent criteria (PMID: 33844962; 38190127). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant for Marfan syndrome (PM1, PM5, PP2, PP3, PP4 with weighted strength, PM2_P). |