In recent years, next-generation sequencing (NGS) platforms that facilitate generation of a vast amount of genomic variation data have become widely used for diagnostic purposes in medicine. However, identifying the potential effects of the variations and their association with a particular disease phenotype is the main challenge in this field. Several strategies are used to discover the causative mutations among hundreds of variants of uncertain significance. Incorporating information from

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... thy population databases, other organisms' databases, and computational prediction tools are evolution-based strategies that give valuable insight to interpret the variant pathogenicity. In this chapter, we first provide an overview of NGS analysis workflow. Then, we review how evolutionary principles can be integrated into the prioritization schemes of analyzed variants. Finally, we present an example of a real-life case where the use of evolutionary genetics information facilitated the discovery of disease-causing variants in medical genomics.