ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4454G>C (p.Cys1485Ser) (rs111978932)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232283 SCV000283629 likely pathogenic Marfan syndrome 2016-03-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 1485 of the FBN1 protein (p.Cys1485Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. 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 affects a cysteine residue located within an epidermal-growth-factor (EGF)-like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although additional genetic data is necessary to definitively confirm the pathogenicity of this variant, cysteine substitutions located in FBN1 EGF-like domains are likely deleterious. For these reasons, it has been classified as Likely Pathogenic.

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