ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2669G>A (p.Cys890Tyr) (rs1555399144)

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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 RCV000663566 SCV000786877 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000498470 SCV000589513 pathogenic not provided 2018-10-03 criteria provided, single submitter clinical testing The pathogenic C890Y variant in the FBN1 gene has not been published as a pathogenic variant, nor has it beenreported as a benign variant to our knowledge. However, different missense variants affecting the same residue(C890R, C890G, C890W) have been reported in the literature in association with Marfan syndrome and ectopia lentis(Kielty et al., 1995; Arbustini et al., 2005; Aragon-Martin et al., 2010. This variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The C890Y variant is a non-conservativeamino 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 insilico analysis predicts this variant is probably damaging to the protein structure/function. In addition, the C890Yvariant is located within the TB4 domain of the FBN1 gene and is predicted to disrupt disulfide bonding with residueC876. Furthermore, missense variants in nearby residues (A882V, C887Y, C896Y) have been reported in the HumanGene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), further supporting the functionalimportance of this region of the protein. In summary, C890Y in the FBN1 gene is interpreted as a pathogenic variant.

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