ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4259G>T (p.Cys1420Phe) (rs397515804)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000663704 SCV000787039 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000489946 SCV000577615 likely pathogenic not provided 2016-05-02 criteria provided, single submitter clinical testing The C1420F variant in the FBN1 gene has been reported in associated with Marfan syndrome (Collod-Beroud et al., 2003; Stheneuer et al., 2009). Stheneuer et al. studied 586 French individuals with the clinical diagnosis of Marfan syndrome and identified one individual with the C1420F de novo variant. Furthermore, the C1420F was not present in 200 control individuals (Stheneuer et al., 2009). C1420F results in a non-conservative amino acid substitution of Cysteine at a position that is conserved across species. A variant in the same residue (C1420W) and in nearby residues (L1421F, P1424A, P1424S) have been reported in HGMD in association with Marfan syndrome (Stenson P et al., 2014), further supporting the functional importance of this region of the protein. The C1420F variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1, 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, the C1420F 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

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