ABSTRACT TMEM17 encodes a transition zone protein essential for ciliary function. Three cases with homozygous variants in TMEM17 in primary ciliopathies (Joubert and Oral‐Facial‐Digital syndrome) have been reported. We investigated whether biallelic TMEM17 variants contribute to primary ciliopathies. We queried our Biodatabank and evaluated the gene‐disease relationship (GDR) according to the ClinGen recommendations. Four unrelated patients (four families) were identified with a clinical diagnosis of Meckel‐Gruber syndrome (MGS) and novel homozygous variants: NM_198276.3:c.4del p.(Glu2Serfs*58); NM_198276.3:c.366dup p.(Pro123Thrfs*9); and NM_198276.3:c.368C>G p.(Pro123Arg). A fifth family lost three foetuses with MGS phenotype, both parents are heterozygote carriers (NM_198276.3:c.4del p.(Glu2Serfs*58)) but biological material from the foetuses was not available. The cases in this study had a severe prenatal phenotype, including encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality. This study strengthens the gene‐disease association of TMEM17 , upgrading it from “limited” to “moderate.” We expand the phenotypic spectrum, ranging from MGS—with prenatal onset and early lethality—to Oral‐Facial‐Digital and Joubert syndromes. Our findings indicate that loss‐of‐function variants may underlie the most severe TMEM17 ciliopathy manifestations, suggesting a potential genotype-phenotype correlation.