The NM_000138 c.4466A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at amino position 1489. This variant has not been reported in the literature but has been reported in ClinVar three times as a variant of uncertain significance (Variation ID: 373598). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID: 31227806) the PM1 criterion has not been used. It is not present in gnomAD v2.1.1 nor v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear about the predicted impact of this variant (REVEL = 0.556). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Another missense variant at the same position (p.Asn1489Lys) is classified as likely pathogenic (PM5; PMIDs: 20082464, 26621581; 21542060). Due to the insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM2_supporting, PP2, PM5.