Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756137 | SCV000883858 | likely pathogenic | not provided | 2018-04-17 | criteria provided, single submitter | clinical testing | The FBN1 c.3533A>G; p.Tyr1178Cys variant is reported in the medical literature in at least one individual with familial classical Marfan syndrome (Stheneur 2009). The variant is also listed in three individuals in the FBN1 variant database (see link below). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a cysteine residue in one of the calcium binding EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Considering available information, this variant is classified as likely pathogenic. References: Link to FBN1 UMD database: http://www.umd.be/FBN1/ Loeys et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 2010 47(7): 476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Wu et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem. Biol. 1995 2(2):91-7. |
| Labcorp Genetics |
RCV001861731 | SCV002309650 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2021-11-14 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1178 of the FBN1 protein (p.Tyr1178Cys). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843, 32679894). 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. 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: 549171). |
| Center for Medical Genetics Ghent, |
RCV000663648 | SCV000786975 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |