ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV001211039 SCV001382560 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1186 of the FBN1 protein (p.Tyr1186Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 19293843, Invitae). ClinVar contains an entry for this variant (Variation ID: 495594). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Medical Genetics Ghent,University of Ghent RCV000663651 SCV000786978 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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