ClinVar

Description

The FBN1 c.5872T>A; p.Cys1958Ser variant is reported in the literature in an individual affected with Marfan syndrome (Mohammad 2018). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 1958 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.917). Additionally, other amino acid substitutions at this codon (p.Cys1958Arg, p.Cys1958Tyr) have been reported in individuals with Marfan syndrome or related aortopathies and are considered disease-causing (Ogawa 2011, Valencia 2015, Yang 2016). 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). Therefore, this variant is classified likely pathogenic. References: Loeys et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 47(7): 476-85. Mohammad et al. Patient with Marfan Syndrome and a Novel Variant in FBN1 Presenting with Bilateral Popliteal Artery Aneurysm. Case Rep Genet. 2018 Mar 29;2018:6780494. Ogawa N et al. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. Am J Cardiol. 2011 Dec 15;108(12):1801-7. Valencia CA et al. Clinical Impact and Cost-Effectiveness of Whole Exome Sequencing as a Diagnostic Tool: A Pediatric Center's Experience. Front Pediatr. 2015 Aug 3;3:67. Wu et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol 1995 2(2):91-7. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002.