ClinVar

Description

A novel G1418C variant that is likely pathogenic was identified in the FBN1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G1418C variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The G1418C 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 within the EGF-like domain 24. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (C1408R, C1420F, C1420W, C1421F, P1424A) 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. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.