Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Center for Human Genetics, |
RCV000659613 | SCV000781452 | pathogenic | Congenital contractural arachnodactyly | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000659613 | SCV000949725 | pathogenic | Congenital contractural arachnodactyly | 2020-11-21 | 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). For these reasons, this allele has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been observed in individuals with congenital contractural arachnodactyly (PMID: 19006240, Invitae). ClinVar contains an entry for this variant (Variation ID: 547356). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 1156 of the FBN2 protein (p.Cys1156Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. |