ClinVar

Description

The p.C1240Y variant (also known as c.3719G>A), located in coding exon 28 of the FBN2 gene, results from a G to A substitution at nucleotide position 3719. The cysteine at codon 1240 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and 7 of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). Based on internal structural analysis, p.C1240Y is predicted to eliminate a conserved disulfide in the cb EGF-like domain #15, suggesting disruption of folding of this domain (Downing AK et al. Cell. 1996;85:597-605). In one study, this variant was reported in a child with Beals syndrome (also known as congenital contractural arachnodactyly (CCA)), and the authors described the occurrence to be de novo (Semyachkina AN et al. Russian Bulletin of Perinatology and Pediatrics. 2016;61(5):47-51 [In Russian]). Another alteration involving the same amino acid, p.C1240R (referred to as p.C1239R), also has been reported in a patient with CCA (Gupta PA et al. Hum Mutat. 2002;19:39-48). This amino acid position is highly conserved in available vertebrate species. In addition, p.C1240Y is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.