ClinVar

In 5 affected individuals from 3 unrelated families with congenital heart defects and skeletal malformations (CHDSKM; 617602), including an African American father and daughter, a European Caucasian father and daughter, and a 5-year-old boy of European Caucasian and Native American descent, Wang et al. (2017) identified heterozygosity for a c.734A-G transition (c.734A-G, NM_007313.2) in the ABL1 gene, resulting in a tyr245-to-cys (Y245C) substitution at a highly conserved residue. The residue, which is 1 of 2 tyrosine residues required for autophosphorylation-induced activation of ABL1 intrinsic kinase activity, is present in both ABL1 isoforms and corresponds to Y226 in isoform 1a. The variant segregated with disease in each of the 3 families, and was shown to have arisen de novo in 2 of them. The authors noted that a similarly affected proband who declined to enter the study was also heterozygous for the Y245C mutation, which was not found in the ExAC database. Immunoblot analysis of transiently transfected HEK293T cells showed increased phosphorylation with the Y245C variant, suggesting increased ABL1 kinase activity.