GTF3C5 encodes transcription factor IIIC63 (TFIIIC63), an integral component of the TFIIIC2 DNA-binding subcomplex essential for RNA polymerase III (Pol III)-mediated transcription 1. It directly binds tRNA and viral promoters to recruit TFIIIB and Pol III, facilitating transcription of small noncoding RNAs including tRNAs and 5S rRNA [UniProt/GO annotations]. GTF3C5 additionally interacts with transcription factors including NFκB-p65 to direct site-specific DNA methylation 2. Biallelic GTF3C5 variants cause a multisystem developmental disorder characterized by growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, and skeletal abnormalities 1. Affected individuals show reduced TFIIIC63 protein levels and approximately 40% reduction in Pol III occupancy at target genomic regions, indicating partial transcriptional impairment 1. GTF3C5 mutations also contribute to pigmentary mosaicism when present as compound heterozygous germline variants 3. Common GTF3C5 variants associate with lipid metabolism and cardiovascular phenotypes, with specific variants enriched in Finnish populations linked to reduced LDL cholesterol concentrations 4. GTF3C5 variants also influence polycythemia vera susceptibility in conjunction with GFI1B 5 and correlate with type 2 diabetes-associated skeletal muscle dysfunction through endoplasmic reticulum stress pathways 6. Additionally, GTF3C5 expression changes occur in pancreatic islets during β-cell death, suggesting relevance to diabetes pathogenesis 7.