The NM_00138 c.1630G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by arginine at amino acid 544 (p.Gly544Arg). This variant impacts a critical glycine between Cys2 and Cys3 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant has been reported twice in ClinVar: once as pathogenic, and once as uncertain significance (Variation ID: 495558). This variant has been previously reported in at least 1 individual with clinical features of Marfan syndrome (MFS) (Invitae lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different nucleotide change resulting in the same amino acid substitution, missense variant at this position, c.1630G>C p.Gly544Arg, has previously been previously established as pathogenic, and was found to segregate with MFS with or without thoracic aortic aneurysm in eight affected individuals from one family (PS1; PMID 30087447, internal lab data). A different missense variant at this position, c.1630G>C p.Gly544Arg, has been found in an individual with a clinical diagnosis of MFS, and has been established as likely pathogenic (PM5; internal lab data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.918). 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: PS1, PM1, PM5, PM2_Sup, PP2, PP3.