53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 2 patients were found to have the above mutation (c.208G>T). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease.

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. The E70* (c.208G>T) mutation was detected in the patient, referred to in the paper by c.421G>T due to a difference in transcript sequence. This nonsense variant was found in a VHL type 1 patient with CNS hemangioblastomas (family ID 4479).

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summariezed the phenotypes of the families together. Family 2 was found with p.Glu70* mutation in the VHL gene: 1/2 members had CNS hemangioblastoma. 1/2 had retinal angioma, and 1/2 members had a pancreatic lesion. ACMG PP4

PatientID: None

KindredID: 4479

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, retinal capillary hemangioma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.E70* (c.208G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.E70* (c.421G>T)

ClinVarID: 428806 https://www.ncbi.nlm.nih.gov/clinvar/variation/428806/

CAID: CA16602179 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.208G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E70* (c.208G>T)

MultipleGeneVariants: N/A