The authors described the growth kinetics of 96 renal tumours in 64 VHL patients (32 males, 32 females). All patients had VHL disease with renal involvement. 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 patients, at least one or more RCC was diagnosed. However, at the time of diagnosis, an indication for treatment was not yet present. For all patients, several CT/MRI scans existed for retrospective description of tumour growth kinetics. 10-ml EDTA anticoagulated blood samples were available from each patient for mutation screening of all exons of the VHL gene. Genomic DNA from blood samples was extracted using standard methods. Small deletions/insertions or point mutations were identified by DNA sequencing followed by complete mutation screening using PCR/single-strand conformation polymorphism and denaturing high-performance liquid chromatography. A germline missense variant p.H115R(c.344A>G) was identified in patient #12. This mutation was noted as c.557A>G in the paper due to a difference in reference transcript used (see Table S1). No family information is available for this patient.

PatientID: 8

KindredID: 3

Case: Sex Unknown, 9Y3M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0009711, HP:0009715, HP:0010797, HP:0002666, HP:0005584 (retinal capillary hemangioma, papillary cystadenoma of the epididymis, hemangioblastoma, pheochromocytoma, renal cell carcinoma)

CaseHPOFreeText: At first presentation (age 5Y6M) the patient had a visual acuity of 20/125. The retinal angioma showed an endophytic growth pattern and was located in the temporal disc margin. Before age 5, the patient had experienced epidydimal cystadenoma and hemangioblastoma of the central nervous system. Either at first presentation or on follow-up the patient presented with renal cell carcinoma, pheochromocytoma, and hemangioblastoma of the CNS.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115R (c.344A>G)

LegacyVariant: p.H115R (c.557A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 664415 https://www.ncbi.nlm.nih.gov/clinvar/variation/664415/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: H115R (c.344A>G)

MultipleGeneVariants: N/A

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. Two patients with VHL-related retinal angiomatosis were found to have germline missense (c.344A>G) mutation in the VHL gene. 1 other affected relative was also evaluated for one of the patients and was found to have the mutation but phenotypes were not described. This variant was reported as c.557A>G (AF010238.1) and mapped to p.H115R (c.344A>G) (NM_000551.3).

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. One female patient, patient 112, was found with this germline mutation from family #40. Shee was diagnosed with a CNS hemangioblastoma at 34Y, renal cell carcinoma at 44Y, and multiple pancreatic cysts/tumors at 44Y. This kindred was likely also published in a later paper by Wang et al., 2018 (PMID: 29330336).

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This missense mutation was found in a German, VHL type 1 family of 2. Both patients had hemangioblastomas of the central nervous system, renal cysts, pancreatic cysts, and cystadenomas of the epididymis (family VHL 60). Also, 1/2 patients had retinal angioma, renal cell carcinoma and liver angiomas. The H115R (c.344A>G) mutation was detected in the patient, referred to in the paper by c.557A>G due to a difference in transcript sequence. This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).