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ARL3 is implicated in Joubert syndrome through autosomal-recessive inheritance. Exome sequencing of two unrelated families with clinically confirmed JBTS identified biallelic missense variants c.445C>T (p.Arg149Cys) and c.446G>A (p.Arg149His) in a highly conserved Arg149 residue, each co‐segregating with disease in consanguineous pedigrees ([PMID:30269812]). Functional assays demonstrate these variants disrupt ARL3 interaction with its guanine nucleotide exchange factor ARL13B, leading to reduced ciliary localization of INPP5E and NPHP3 in patient‐derived cells, consistent with a loss‐of‐function mechanism ([PMID:30269812]). No conflicting reports have been described. Collectively, this evidence yields a Limited ClinGen classification, supported by two probands with biallelic ARL3 variants and concordant cellular data. ARL3 should be included in diagnostic JBTS gene panels when common causes are excluded. Key take-home: Biallelic ARL3 missense mutations at Arg149 cause Joubert syndrome by disrupting ciliary protein composition.
Gene–Disease AssociationLimited2 unrelated probands with biallelic ARL3 missense variants leading to Joubert syndrome, supported by co-segregation and functional data ([PMID:30269812]) Genetic EvidenceLimitedTwo probands from consanguineous families with autosomal-recessive inheritance and homozygous ARL3 Arg149 variants ([PMID:30269812]) Functional EvidenceModerateCell‐based assays show Arg149 variants disrupt ARL3–ARL13B interaction and mislocalize INPP5E/NPHP3 in cilia ([PMID:30269812]) |