ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.811T>G (p.Cys271Gly) (rs1060501019)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465059 SCV000544825 likely pathogenic Marfan syndrome 2016-07-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 271 of the FBN1 protein (p.Cys271Gly). 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 has been reported in individuals in the Universal Mutation Database (PMID: 22144684). 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.
GeneDx RCV000493552 SCV000582432 likely pathogenic not provided 2015-10-15 criteria provided, single submitter clinical testing Although the C271G variant has not been published as a pathogenic variant or as a benign variant, to our knowledge, it was previously identified by Béroud et al. (2000) in one individual with Marfan syndrome where it was classified as a pathogenic variant; no additional clinical information was available. This variant 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. The C271G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, the C271G variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, missense variants in nearby residues (G267R, N280T) have been reported in the Human Gene Mutation Database in association with FBN1-related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic

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