ClinVar

Description

The I1909T variant in the FBN1 gene has been reported previously in a seven year-old male meeting diagnostic criteria for Marfan syndrome (Loeys et al., 2001). Additionally, this variant was listed in a study validating the detection of mutations in individuals with Marfan and Loeys-Dietz syndrome by massive parallel sequencing (Baetens et al., 2011). This variant has been observed in one other individual referred for genetic testing of Marfan syndrome/TAAD at GeneDx. The I1909T 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. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Missense variants in nearby residues have been reported in association with Marfan syndrome (Stenson et al, 2014). However, while the I1909T variant is located in a calcium-binding EGF-like domain of the fibrillin-1 protein, it does not affect a Cysteine residue within this domain. Cysteine substitutions in calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.In summary, additional evidence is needed to determine whether this variant is pathogenic or a rare benign variant