The genomic revolution and widespread availability of next generation sequencing for rare diseases has driven genetic discovery for more than a decade and now dominantes molecular diagnostic practice. With these advances in our ability to detect rare variants across the entire genome comes increased uncertainty of the impact of many variants and genotypes. Standardization of variant interpretation (ACMG/AMP guidelines) often leads to uncertainty (variants of uncertain significance) and the importance for many genes in disease is unclear. The overall aim of the ClinGen Gene Curation Expert Panels (GCEP) and the Variant Curation Expert Panels (VCEP) is to provide gene and variant level expert guidance for interpretation of genetic results for clinicians, clinical scientists, molecular geneticists and counsellors. Here, we will explore the process of gene and variant curation with case studies to highlight some of the challenges.