ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3467G>T (p.Cys1156Phe) (rs1206843725)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659613 SCV000781452 pathogenic Congenital contractural arachnodactyly 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000659613 SCV000949725 likely pathogenic Congenital contractural arachnodactyly 2018-09-21 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with congenital contractural arachnodactyly (PMID: 19006240, Invitae). ClinVar contains an entry for this variant (Variation ID: 547356). 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 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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