A missense mutation in is associated with decreased risk for congenital heart defects and may increase cellular uptake of vitamin B12 via Megalin.

Deregulation of folate and vitamin B12 (VB12) metabolism contributes to the risk of congenital heart defects (CHDs). Transcobalamin (TCN2) is essential for transporting VB12 from blood to cells as TCN2-bound VB12 (holo-TC) is the only form for somatic cellular uptake. In this study, we performed an association study between common polymorphisms in 46 one carbon metabolism genes and CHD in 412 CHDs and 213 controls. Only two significant association signals in coding regions were identified: FTCD c.1470C>T & TCN2 c.230A>T. The only missense mutation, TCN2 c.230A>T, was further validated in 412 CHDs and 1177 controls. TCN2 c.230T is significantly associated with reduced CHD risk in North Chinese (odds ratio = 0.67, = 4.62e-05), compared with the 230A allele. Interestingly, the mean level of plasma holo-TC in women with the TA genotype was 1.77-fold higher than that in women with the AA genotype. Further analysis suggested that c.230A>T enhanced the cellular uptake of holo-TC via the LRP2 receptor. Our results determined that a functional polymorphism in TCN2 contributes to the prevalence of CHDs. TCN2 c.230A>T is significantly associated with a reduced CHD risk, likely due to TCN2 c.230T improving the interaction between holo-TC and its LRP2 receptor.