ClinVar

Description

The G125R missense mutation in the TBX5 gene has been reported in association with atypical Holt-Oram syndrome (HOS) and paroxysmal atrial fibrillation, where it was found to co-segregate with disease in affected family members (Postma et al., 2008). In contrast to all currently known missense mutations in the TBX5 gene, in vitro assays suggest G125R acts as a gain-of-function mutation. It 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. G125R 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. In addition, missense mutations in nearby residues (D111Y, W121G) have been reported in association with Holt-Oram syndrome, supporting the functional importance of this region of the protein. This variant was found in TBX5