ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1670G>A (p.Cys557Tyr) (rs1057521102)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443014 SCV000521074 likely pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing A variant that is likely pathogenic was identified in the FBN1 gene. The C557Y variant has been reported in association with Marfan syndrome (Stheneur et al., 2009); however, detailed clinical information was not provided. This variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The C557Y 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. Furthermore, 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. Finally, the C557Y 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).
Invitae RCV000631988 SCV000753091 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-01-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 557 of the FBN1 protein (p.Cys557Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant has been reported in an individual affected with classical Marfan syndrome (PMID: 19293843). ClinVar contains an entry for this variant (Variation ID: 381611). This variant affects a cysteine residue located within a hybrid motif domain of the FBN1 protein. Cysteine residues in these domains are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions within the hybrid motif domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663479 SCV000786778 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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