NM_000138.5 c.6448C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 2150 (p.Arg2150Cys). This variant has been identified in more than 15 patients with features suggestive of, or consistent with, Marfan syndrome (MFS), including at least three who meet clinical diagnostic criteria for MFS and more than 10 individuals who do not meet MFS diagnostic criteria but have thoracic aortic aneurysm and dissection (TAAD), with or without additional clinical features of MFS (PS4, PP4; Bichat, University of Tokyo, UZA, Invitae, & GeneDx internal data; PMIDs: 37042257, 19161152, 37558401, 33059708, 31730815). The variant was found to segregate with a clinical diagnosis of MFS in one patient’s parent, and with mild features suggestive of MFS or another connective tissue disorder in approximately 11 affected family members between two additional families (PP1_strong; UZA & Invitae internal data); notably, this variant is associated with particularly variable expressivity and incomplete penetrance of the MFS phenotype. It is present in gnomAD with a maximum frequency of 0.0008% (1/113462 alleles European, non-Finnish; https://gnomad.broadinstitute.org/, v2.1.1). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.923). 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: PS4, PP1_strong, PM1, PP2, PP3, PP4.