ClinVar

Description

p.Pro1521Thr (CCA>ACA): c.4561 C>A (NM_000138.4) The P1521T variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. P1521T results in a non-conservative amino acid substitution of a non-polar Proline residue for a polar Threonine residue at a position that is highly conserved across species. Other missense mutations in nearby residues (C1526S, C1526Y, D1528Y) have been reported in association with Marfan syndrome or other FBN1-related disorders, supporting the functional importance of this region of the protein. The P1521T 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. In silico algorithms are not consistent in their predictions but at least two concur that P1521T is damaging to the protein structure/function.Therefore, based on the currently available clinical and molecular information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).