NM_000138.5 c.6446A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine amino acid 2149 (p.Tyr2149Cys). This variant has been identified in at least 13 individuals with features suggestive of, or consistent with, Marfan syndrome (MFS), including four patients meeting clinical diagnostic criteria for MFS, seven with thoracic aortic aneurysm or dissection (TAAD) with or without additional features of MFS, and two with unspecified clinical suspicion of MFS (PS4, PP4; Johns Hopkins, University of Texas-Houston, LMM, & Invitae internal data; PMIDs: 24793577, 27611364, 37684520, 31098894). The variant was found to be de novo in five of these patients, including three (maternity/paternity assumed) with phenotypes consistent with, but not highly specific to, FBN1, one (maternity/paternity assumed) with TAAD and borderline systemic involvement, and one (maternity/paternity confirmed) with a non-specific and genetically heterogeneous phenotype of TAAD and mitral valve prolapse (PS2; Johns Hopkins & Invitae internal data; PMIDs: 31098894, 37684520). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a conserved residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.900). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). 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: PS2, PS4, PM1, PP2, PP3, PP4, PM2_supporting.