Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002310863 | SCV000319304 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2014-07-14 | criteria provided, single submitter | clinical testing | The p.C2295Y pathogenic mutation (also known as c.6884G>A), located in coding exon 56 of the FBN1 gene in the cb EGF-like#36 domain, results from a G to A substitution at nucleotide position 6884. The cysteine at codon 2295 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation was first reported in a cohort of individuals with known sequence changes in the FBN1 gene; however, clinical details were not provided (Matyas G et al. Hum Mutat. 2002;19(4):443-56). In addition, this pathogenic mutation was described in an individual who met Ghent criteria and did not show features suggestive of Loeys-Dietz syndrome (Aalberts JJ et al. Gene. 2014;534(1):40-3). A different amino acid substitution at the same position, p.C2295R, has also been reported as a disease-causing mutation (Voermans NC et al. Clin Genet. 2009;76(1):25-37). 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). Based on the supporting evidence, p.C2295Y is interpreted as a disease-causing mutation. |
| Invitae | RCV000631910 | SCV000753013 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-08-14 | criteria provided, single submitter | clinical testing | 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: 263849). This missense change has been observed in individuals with Marfan syndrome (PMID: 11933199, 24161884). 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 2295 of the FBN1 protein (p.Cys2295Tyr). |
| Center for Human Genetics, |
RCV000659572 | SCV000781407 | pathogenic | Marfan syndrome | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Centre of Medical Genetics, |
RCV000659572 | SCV002025423 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PVS2, PP4 |
| Center for Medical Genetics Ghent, |
RCV000659572 | SCV000787277 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |