ClinVar

Description

NM_00138 c.1708T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 570 (p.Cys570Arg). This variant has been found in two probands with ectopia lentis (EL), one of whom was also reported to have numerous systemic features of Marfan syndrome without thoracic aortic aneurysm and dissection (TAAD), as well as a proband with isolated TAAD (PS4_moderate; PMID: 10486319; 3billion & Invitae internal data, ClinVar Variation ID: 956400). An additional proband with a severe Marfan syndrome phenotype including EL, TAAD, and major skeletal involvement (PP4; Bichat internal data). Functional studies performed on patient fibroblasts with this variant demonstrated reduced fibrillin synthesis and secretion (50% and 28% of controls, respectively) (PS3_supporting; PMID: 10486319). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). 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). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys570Gly, p.Cys570SerSer, p.Cys570Trp, p.Cys570Tyr). Computational prediction tools and conservation analysis support that this variant may impact the protein’s structure or function (PP3). 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: PM1_strong, PS4_moderate, PS3_supporting, PM2_supporting, PP2, PP3, PP4.