ClinVar

Description

The p.C908Y pathogenic mutation (also known as c.2723G>A), located in coding exon 22 of the FBN1 gene, results from a G to A substitution at nucleotide position 2723. The cysteine at codon 908 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the hybrid motif #02 domain. This alteration was shown to segregate with Marfan syndrome (MFS) in several members of a family. The proband, who was reported to also have MFS, did not carry this alteration, but the clinical diagnosis was described as debatable (Judge DP et al. Am J Med Genet. 2001;99:39-47). This alteration has also been reported in individuals with ectopia lentis or thoracic aortic aneurysm and dissection (Li D et al. Genet Test. 2008;12:325-30; Wang WJ et al. J Mol Med. 2013;91:37-47). Alterations at the same amino acid position, C905G and C908R, have also been detected in patients with MFS (Haine E et al. J Bone Miner Res. 2015;30:1369-76; Katzke S et al. Hum Mutat. 2002;20:197-208; Stheneur C et al. Eur J Hum Genet. 2009;17:1121-8). 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). And internal structural analysis indicates that p.C908Y eliminates a conserved disulfide motif in TB-hybrid domain 2 of fibrillin-1, which is expected to result in a more dynamic structure in this part of the protein (Jensen SA et al. Structure. 2009;17:759-68). Based on the available evidence, C908Y is classified as a pathogenic mutation.