ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3557A>G (p.Tyr1186Cys) (rs1555398511)

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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 RCV000663651 SCV000786978 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589146 SCV000695519 uncertain significance not provided 2016-05-12 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.3557A>G (p.Tyr1186Cys) variant involves the alteration of a conserved nucleotide located in a conserved region within EGF-like #14. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. In support of a deleterious effect of this variant, 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index) and the variant is absent in 120500 control chromosomes. The variant was detected in one classicial MFS patient in the literature (Stheneur_2009). Therefore, the variant was classified as a VUS - possibly pathogenic variant.

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