ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1849T>G (p.Cys617Gly) (rs1060501017)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474956 SCV000544823 likely pathogenic Marfan syndrome 2016-10-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 617 of the FBN1 protein (p.Cys617Gly). 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). This variant has been reported in an individual affected with Marfan syndrome (PMID: 21542060). 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 TGFBP 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: 11104663, 12203987, 16677079). In addition, missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). In summary, this variant is a previously reported missense change affecting a residue crucial for protein stability and function. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, cysteine substitutions located in FBN1 TGFBP domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000474956 SCV000786805 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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