ClinVar

Description

The NM_00138 c.2287T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 763 (p.Cys763Arg). This variant has been reported 3 times in ClinVar, twice as likely pathogenic and once as uncertain significance (Variation ID: 519758). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.979) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup, PP2, PP3