ClinVar

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1384 of the FBN2 protein (p.Cys1384Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN2-related conditions (PMID: 19006240, 31316167). ClinVar contains an entry for this variant (Variation ID: 196780). 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. 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). This variant disrupts the p.Cys1384 amino acid residue in FBN2. Other variant(s) that disrupt this residue have been observed in individuals with FBN2-related conditions (PMID: 19006240, 31316167), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.