Algorithms and guidelines for interpretation of DNA variants

Abstract

With the increasing amount of molecular genetic testing offered for clinical diagnosis in recent years, there is a rapid growth in the detection of novel or unclassified variants of unknown clinical significance. To determine whether a sequence change is a disease-causing pathogenic mutation or a non-causative variant becomes increasingly important in translational medicine. Interpretation of the clinical significance of an unclassifi ed variant in the mitochondrial genome is even more complicated due to the highly polymorphic feature of the mitochondrial DNA and the unique characteristics of heteroplasmy. The degree of mutant mitochondrial DNA heteroplasmy varies among different tissues; in general, it correlates with the disease severity in affected tissues. In this chapter, we provide updated procedures of evaluating unclassified variants in both the nuclear and mitochondrial genomes by using various databases, computational tools, and structural analysis methods to assist in clinical interpretation.