Submissions for variant NM_000138.5(FBN1):c.3557A>G (p.Tyr1186Cys)

dbSNP: rs1555398511

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663651	SCV004218514	pathogenic	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	NM_000138.5 c.3557A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by a cysteine at amino acid 1186 (p.Tyr1186Cys). It has been identified in at least five individuals with diagnoses or suspicion of Marfan syndrome including the following: a pediatric patient with bilateral ectopia lentis (EL), severe thoracic aortic aneurysm and dissection (TAAD), and a systemic score of 9; an adult patient with EL and a systemic score of 6; a patient with bilateral EL, TAAD, and systemic features; an individual reported to have Marfan syndrome without specific details provided; and an individual with bilateral EL, TAAD, retinal detachment, and systemic features (PS4; PMIDs: 31061752, 11933199; UZG, Bichat, & Invitae internal data). It was also found to segregate with Marfan syndrome in two other members of an aforementioned family (PP1; Bichat internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.974). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PP1, PP2, PP3, PM2_supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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. 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. 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"). 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). This variant is not present in population databases (ExAC no frequency).
Center for Medical Genetics Ghent, University of Ghent	RCV000663651	SCV000786978	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing