The NM_00138 c.1468G>T is a missense variant in FBN1 predicted to cause a substitution of a aspartic acid by tyrosine at amino acid 490 (p.Asp490Tyr). This variant impacts an aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (PMID 35058154, internal lab data, PP4). This variant has been reported three times in ClinVar: twice as pathogenic and once as uncertain significance (Variation ID: 549019). This variant has also been identified in at least 2 individuals with a clinical diagnosis of MFS as well as in an individual with clinical features of MFS (PMID 11826022, 20886638, Invitae ClinVar entry; PS4_Mod). A different missense variant at this position, c.1468G>C (p.Asp490His), has previously been previously established as (likely) pathogenic and has been found in at least 3 individuals with clinical features of MFS and was found to segregate with disease (PMID 25652356, internal data; PM5), Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.965, PP3). This variant is located in the last nucleotide of the exon. In silico prediction programs predict that this variant may disrupt RNA splicing (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_Moderate, PM2_Sup, PP2, PP3, PP4.