The NM_00138 c.5743C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1915 (p.Arg1915Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband with classical Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 6 times in ClinVar: once as pathogenic, 4 times as likely pathogenic, and once as uncertain significance (Variation ID: 495629). This variant has also been identified in at least 7 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 27234404, 35916808, 33174221, 27906200, internal data; PS4). In two families with MFS, the variant was found to segregate with disease in three affected relatives (Internal lab data, PP1). Different missense variants at this position, c.5744G>A p.(Arg1915His) and c.5743C>A p.(Arg1915Ser), have previously been reported in individuals with MFS and/or MFS-related features (PMID 11700157, 31830381), however these variants have not yet been reviewed by the FBN1 Variant Curation Expert Panel. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant's protein function and structure (REVEL: 0.62). 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, PM2_Sup, PP2, PP4.