NM_000138.5 c.3476G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1159 (p.Cys1159Tyr). This variant was found in a 2-year-old proband with thoracic aortic aneurysm (TAA), ectopia lentis, and a systemic score ≥ 7, which is a highly specific phenotype for Marfan syndrome (MFS) (PP4; UZG internal data). This variant has been reported 3 times in ClinVar as pathogenic (2) and of uncertain significance (1) (Variation ID: 547309). This variant has been identified in 4 other individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS, as de novo in a neonate with severe TAA and a systemic score of 6, and in 2 additional individuals who did not meet diagnostic criteria either but have phenotypes strongly suggestive of MFS (PS4, PM6_supporting; PMIDs: 35831148, 31523900, 34628919; UZG, Mayo, & Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL = 0.981). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). 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_strong, PP2, PP3, PP4, PM2_supporting, PM6_supporting.