Technological innovation related to the advent and development of the Next-Generation Sequencing (NGS) has provided significant advances in the diagnosis of disorders with genetic and phenotypic variability, such as neurodegenerative diseases. However, the interpretation of NGS data often remains challenging, although advanced prediction tools have contributed to primarily assess the impact of some missense variants. Here, we report a patient with Parkinson's disease (PD) and a family history of disease, in which a panel of 29 disease-causing or risk genes for PD were analyzed. We identified a new missense variant in the SNCA gene. Although this variant might be associated with PD in this family, it has been currently classified as a "Variant of Unknown Significance" because of the lack of segregation with disease. Indeed, we subsequently found the same mutation in an unaffected sister. Nevertheless, this finding may help clinicians and researchers in questioning the causative role of genetic variants within the daily clinical and diagnostic settings.