ClinVar

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1268 of the FBN2 protein (p.Cys1268Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of congenital contractural arachnodactyly (Invitae). ClinVar contains an entry for this variant (Variation ID: 1003634). 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 FBN2 protein function with a positive predictive value of 80%. This variant affects a cysteine residue located within an epidermal growth factor (EGF)–like domain of the FBN2 protein. Cysteine residues in these domains are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN2 EGF-like domains affecting cysteine residues are overrepresented in patients with congenital contractural arachnodactyly (PMID: 18767143). For these reasons, this variant has been classified as Pathogenic.