As the number of genes available for commercial sequencing increases and the promise of clinical whole-genome sequencing becomes a reality, the interpretation of the results of these tests becomes more challenging for the practicing neurologist as these studies have the potential to detect novel genetic variants. Such reports are becoming more frequent in general practice, and neurologists are often left to puzzle over the relevance of these "variants of unknown significance," as such genetic changes are often described, and how to communicate this information to the patients and their families. This article will briefly illustrate how clinicians can use such results in the care of their patients. Only genetic variants involving coding sequence will be considered, although similar methods may also be applied to changes such as noncoding alterations or copy number variations. It is also important to note that in some cases, particularly those involving tests that only sequence select exons, negative test results may also require special interpretation.