ClinVar

Description

This variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, a different missense variant at the same residue (C1947Y) was reported as a likely pathogenic variant in a 5 year-old male who met criteria for a clinical diagnosis of Marfan syndrome (Lerner-Ellis et al., 2014). In addition, missense variants in nearby residues (F1954C, C1956R) have been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The C1947R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C1947R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, the C1947R variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003).Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.