ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1073G>A (p.Cys358Tyr)

dbSNP: rs1555400606
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen RCV000663439 SCV004123035 likely pathogenic Marfan syndrome 2023-11-16 reviewed by expert panel curation NM_00138 c.1073G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 358(p.Cys358Tyr). This variant has been found in two probands, one with the clinical diagnosis of Marfan syndrome but without a specified phenotype and one with ectopia lentis, thoracic aortic aneurysm and dissection, and a systemic score of 9 (PP4, PS4_supporting; PMID: 35058154; UZG internal data). This variant has been reported two times in ClinVar, once as likely pathogenic and once as of uncertain significance (Variation ID: 549001). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a TGF-beta binding-protein-like (TB) domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). Other variants altering this codon are pathogenic or likely pathogenic (p.Cys358Trp, p.Cys358Arg), supporting the functional importance of this amino acid position (PM5). Computational prediction tools and conservation analysis suggest that this variant may impact protein structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_supporting, PM2_supporting, PP2, PP3, PP4.
Centre of Medical Genetics, University of Antwerp RCV000663439 SCV002025411 likely pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PS5, PP4
Center for Medical Genetics Ghent, University of Ghent RCV000663439 SCV000786729 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.