Abstract The full breadth of the clinical sites research based genomic analyses is resource intensive, requiring bioinformatics personnel and more expensively, a laboratory with computing infrastructure and storage capabilities. With the funding of the clinical sites of the UDN beyond 2022 being uncertain, exploring cost-efficient and at the same time effective strategies for genome analyses at the clinical sites is crucial to maintaining the scientific edge of the network. Our proposed project will evaluate an alternative pipeline for effectiveness and efficiency in the analysis of exome and genome sequencing data at the Duke/Columbia clinical site. We will customize a commercial platform to conform closely to our research pipeline. We will run this pipeline simultaneous to the sequencing core analyses and evaluate the relative effectiveness of this new analysis structure in determining pathogenic and likely pathogenic variants and novel candidate gene variants. If effective, such a paradigm might provide a less resource heavy approach to analyzing genomic data at the clinical sites. We believe that this pilot project will provide a paradigm for analyses of genomic data at the UDN clinical sites while maintaining most of the scientific rigor that has contributed to the diagnostic capabilities of the network and may offer a path forward for sustainability.