ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.406T>G (p.Cys136Gly) (rs1555405041)

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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 Medical Genetics Ghent,University of Ghent RCV000663691 SCV000787023 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Invitae RCV000529377 SCV000627904 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-02-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 136 of the FBN1 protein (p.Cys136Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. 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. 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: 10486319, 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). A different missense substitution at this codon (p.Cys136Ser) has been determined to be pathogenic (PMID: 18435798). This suggests that the cysteine residue is critical for FBN1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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