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We now show that mice with a C4232R missense mutation in Low density lipoprotein receptor related protein 1 (LRP1) exhibit atrioventricular septal defects with double outlet right ventricle. <jats:italic>Lrp1<\/jats:italic><jats:sup><jats:italic>m\/m<\/jats:italic><\/jats:sup> mice exhibit shortened outflow tracts (OFT) and dysmorphic hypocellular cushions with reduced proliferation and increased apoptosis. <jats:italic>Lrp1<\/jats:italic><jats:sup><jats:italic>m\/m<\/jats:italic><\/jats:sup> embryonic fibroblasts show decreased cell motility and focal adhesion turnover associated with retention of mutant LRP1 in endoplasmic reticulum and reduced LRP1 expression. Conditional deletion of <jats:italic>Lrp1<\/jats:italic> in cardiac neural crest cells (CNC) replicates the full CHD phenotype. Cushion explants showed defective cell migration, with gene expression analysis indicating perturbation of Wnt and other signaling pathways. 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