NM_000138.5 c.6662G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2221 (p.Cys2221Tyr). This variant has been reported in three patients, including two with clinical diagnoses of Marfan syndrome and one with ectopia lentis without assessment for additional phenotypes (PP4, PS4_moderate; PMIDs: 26787436, 38190127; Invitae internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). 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 support that this variant is likely to impact the protein (PP3; REVEL = 0.965). 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: PM1_strong, PS4_moderate, PP2, PP3, PP4, PM2_supporting.