Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000232543 | SCV000287270 | uncertain significance | Congenital contractural arachnodactyly | 2016-03-10 | criteria provided, single submitter | clinical testing | 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). In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. However, segregation and functional evidence implicating this variant are not available. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. This sequence change replaces cysteine with tyrosine at codon 2001 of the FBN2 protein (p.Cys2001Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. |