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    A novel missense mutation (N78D) in a family with von Hippel–Lindau disease with central nervous system haemangioblastomas, pancreatic and renal cysts
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    1. ClingenBaseline 23 Oct 2026
      In a family with VHL, we identified a novel missense mutation (N78D), which affects a fully conserved residue in the VHL protein. Interestingly, several other missense mutations reported at same codon in the VHL protein that might be associated with a low risk of renal cell carcinoma (RCC) but not pheochromocytoma appear to be associated with a VHL type 1 phenotype. At the moment, RCC is present in none of the affected mutation carriers in the family described here. In contrast to other missense changes at codon 78, the change in our VHL family is predicted to have a mild effect on VHL function, which apparently is insufficient to cause predisposition to RCC.

      PatientID: II-3

      KindredID: 1

      Case: F, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Reported 3 siblings (II:3, II:6, II:7) of a family clinically diagnosed as having VHL type 1 was identified with the c.232A>G mutation. Two female siblings (II:1, II:2) died from CHB. Three (II:3, II:6, II:7) of the ten siblings had multiple CNS haemangioblastomas, and all tested positive for the mutation. The age of onset for all patients varied from 20 to 25 years, and it was likely inherited from the mother who had died at the age of 40 years due to haemangioblastoma (in the medulla oblongata), and hydrocephalus after having multiple operations.

      CasePresentingHPOs: HP:0009713; HP:0006880; HP:0030393; HP:0001737; HP:0000107 (spinal hemangioblastoma, cerebellar hemangioblastoma; endolymphatic sac tumor; pancreatic cysts; renal cyst)

      CaseHPOFreeText: Patient presented with headache, tinnitus and abdominal pain. She had a history of endolymphatic sac tumors (ELSTs) treated by surgery. She had cerebellar/spinal haemangioblastomas, pancreas and kidney cystic masses.

      CaseNotHPOs: HP:0005584 (renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78D (c.232A>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625226 https://www.ncbi.nlm.nih.gov/clinvar/variation/625226/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: N78D (c.232A>G)

      MultipleGeneVariants: N/A

      InheritancePattern:AutosomalDominant DiseaseEntity:VHL DiseaseEntity:spinalhemangioblastoma DiseaseEntity:cerebellarhemangioblastoma DiseaseEntity:endolymphaticsactumor DiseaseEntity:pancreaticcysts DiseaseEntity:renalcyst ProteinPosition:78 cDNAposition:232 CivicName:N78D(c.232A>G) AminoAcidChange:ASNtoASP MutationType:missense_variant;transition ClinVarID:625226 ClinVarID:Yes AssumedRefSeq:NM_000551.3 Mutation:Germline Familial FamilyPedigree ExperimentalAssay inferred_gene_hgnc:5542 inferred_gene_source:ClinVar VHL Hypothesis Annotation
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    link.springer.com/article/10.1007/s10689-012-9586-7