Objective:To describe a child meeting diagnostic criteria for tuberous sclerosis complex (TSC) carrying a pathogenic somatic variant inRHEB, but no pathogenic variants in the two known TSC genes,TSC1orTSC2.Methods:We present the clinical and imaging findings in a child presenting with drug-resistant focal seizures and multiple cortical tubers, a subependymal giant cell astrocytoma and multiple subependymal nodules in one cerebral hemisphere. Targeted panel sequencing and exome sequencing were performed on genomic DNA derived from blood and resected tuber tissue.Results:The child satisfied clinical diagnostic criteria for TSC, having three major features, only two of which are required for diagnosis. Genetic testing did not identify pathogenic variants or copy number variations inTSC1orTSC2, but identified a pathogenic somaticRHEBvariant (NM_005614.4:c.104_105delACinsTA [p.Tyr35Leu]) in the cortical tuber.Discussion:RHEB is a partner of the TSC1/2 complex in the mechanistic target of rapamycin pathway. Somatic variants inRHEBare associated with focal cortical dysplasia and hemimegalencephaly. We propose that variants inRHEBmay explain some of the genetically undiagnosed TSC cases and may be the third gene for TSC orTSC3.