ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1481G>A (p.Cys494Tyr) (rs1057518881)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423905 SCV000521075 likely pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the FBN1 gene. The C494Y variant has beenreported in at least two patients with Marfan syndrome or suspected Marfan syndrome(McInerney-Leo et al., 2013; Yang et al., 2016); however detailed clinical information was notincluded. This variant was not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The C494Y variant is a non-conservative amino acidsubstitution, 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 acrossspecies, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. Finally, the C494Y variant affects a Cysteine residue within a calcium-bindingEGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter thestructure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domainsrepresent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003).
Invitae RCV000792027 SCV000931299 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 494 of the FBN1 protein (p.Cys494Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Marfan syndrome, or aortic disease (PMID: 28973303, 24501682, 27611364). ClinVar contains an entry for this variant (Variation ID: 381612). This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues 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 affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663462 SCV000786756 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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