ClinVar

Description

The p.C1402W variant (also known as c.4206T>G), located in coding exon 33 of the FBN1 gene, results from a T to G substitution at nucleotide position 4206. The cysteine at codon 1402 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #19 domain. 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 alteration has been reported in a patient with Marfan syndrome, and limited functional studies demonstrated a reduction in fibrillin deposition (Schrijver I et al. Am. J. Hum. Genet., 1999 Oct;65:1007-20). In addition, alternate amino acid substitutions at this position, p.C1402Y and p.C1402R, have also been detected in individuals with Marfan syndrome (Comeglio P et al. Hum. Mutat., 2001 Dec;18:546-7; Arbustini E et al. Hum. Mutat., 2005 Nov;26:494; Pees C et al. Clin. Genet., 2014 Dec;86:552-7). Based on internal structural assessment, these alterations eliminate a structurally critical disulfide bond in cbEGF domain #19. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.