ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1726T>G (p.Cys576Gly) (rs794728174)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181440 SCV000233742 pathogenic not provided 2013-07-16 criteria provided, single submitter clinical testing p.Cys576Gly (TGC>GGC): c.1726 T>G in exon 15 of the FBN1 gene (NM_000138.4) While the Cys576Gly mutation in the FBN1 gene has not been reported to our knowledge, a mutation affecting this same codon, Cys576Tyr, has been reported in association with Marfan syndrome (Attanasio M et al., 2008). Additionally, mutations in nearby residues (Asp574Gly, Cys582Arg, Gly585Arg, Gly585Glu) have been reported in association with Marfan syndrome, further supporting the functional importance of this codon and this region of the protein. Cys576Gly results in a non-conservative amino acid substitution of a polar Cysteine with a non-polar Glycine at a position that is conserved across species. In silico analysis predicts Cys576Gly is damaging to the protein structure/function. Furthermore, Cys576Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Cys576Gly in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Invitae RCV000468400 SCV000544848 likely pathogenic Marfan syndrome 2016-09-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 576 of the FBN1 protein (p.Cys576Gly). 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. ClinVar contains an entry for this variant (Variation ID: 199977). 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: 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). In summary, this variant is a rare 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 EGF-like domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic.

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