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Backgrounds: Retinal capillary hemangioblastoma (RCH) although may also be observed sporadically, is the most frequent and earliest manifestation of the Von Hippel-Lindau disease (VHL). This is the first report of different types of variants spectrum and genotype-phenotype correlations in the Iranian families with RCH. Methods: In this Prospective Observational Case Series study, 17 families with RCH were included. PCR was performed to amplify 3 exons of the VHL gene. Afterwards, Sanger sequencing was performed on all the PCR products. For the detection of VHL copy number variations, MLPA was used. Results: Our study identified 10 different types of predominantly pathogenic VHL variants. Missense mutations were the most common variants located on the α domain of the VHL protein (pVHL) in exon 3. Also, the pathogenic variants in RCH patients with CNS hemangioblastoma (CHB) mostly (72.7%) were located on the α domain. In a family, Proband’s sister had a different mutation with more severe clinical manifestations and a poor prognosis.Conclusion: α domain of VHL may play a potential role in the pathogenesis of RCH. Our findings suggest that the genotype-phenotype characteristics in those variants in α- domain may predispose patients to RCH with CHB.

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