Genetic testing for neurologic indications is becoming increasingly common. While diagnostic yield has improved over time, over 50% of tests ordered for certain neurologic indications continue to result with at least one variant of uncertain significance (VUS).
Extensive guidance has been published on the topic of genetic variant interpretation; nevertheless, it remains a complicated process susceptible to individual biases. In practice, reporting laboratories have shown low levels of concordance even when interpreting the same variant- as low as 39% across 9 laboratories – and over 2/3 of genetic counselors experienced discrepancies between the laboratory report and their own interpretation. By performing clinical variant interpretation on the individual level using thorough chart review, literature review, publicly available tools (ClinVar, ExAc, gnomAD, Mastermind, etc.), and additional clinical studies (family segregation testing, functional studies, muscle biopsies, etc.), some VUS can be reclassified to either pathogenic or benign. The difference between these classifications can give or take away a diagnosis, change patient and family counseling, and dictate management including possible access to gene therapy or clinical trials.
Here we discuss the implementation of clinical variant interpretation in an adult neuromuscular clinic using a series of cases and propose a workflow to apply this to similar clinics. There are barriers, such as lack of clinician time and resources, that prevent the seamless integration of clinical variant interpretation however many of these recommendations can be easily adopted by providers with limited genetics experience via brief self-guided training.