A family with VHL syndrome from a Han Chinese population was recruited for the present study in Hunan Cancer Hospital (Changsha, China). There were originally 23 patients in this pedigree; however, 6 patients succumbed to mortality prior to recruitment. In total, 17 subjects [including 8 males and 9 females; aged 4–65 years old; one patient suffering from VHL syndrome (proband)] were enrolled and underwent detailed clinical examinations. The proband (III:2) was a 28-year-old male, who presented with an episodic headache for 10 years. A cyst and a nodule were revealed via brain MRI. The cyst was demonstrated to be a hemangioblastoma tumor. A heterozygous mutation c.345C>A (p.H115Q) in exon 2 of the VHL gene was revealed to be present in the proband. In addition, two of the proband's maternal cousins were healthy individuals that were demonstrated to carry the mutation, as revealed by Sanger sequencing: III:4, male, and III:8, female. Genomic DNA was isolated from peripheral blood lymphocytes of all subjects using the standard phenol-chloroform method. VHL was amplified via polymerase chain reaction (PCR). Three pairs of primers were designed to cover all of the exons and splicing junctions of VHL. PCR amplification was performed using an ABI 2720 PCR system. Sanger sequencing was performed using an ABI 3100/3130 Genetic Analyzer automated sequencer. The sequencing results were analyzed using SeqMan 3.0. A further five affected members of the family had previously died from this syndrome, including the proband's mother, grandfather, two uncles, and a cousin. ACMG evidence codes: "flag for PP3 review"- Multiple lines of computational evidence support a deleterious effect on the gene/gene product. "flag for PP4 review"- patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Peripheral blood leukocytes were isolated and directly sequenced. Patient 27, 42Y male, with VHL Type 1 presented with bilateral and/or multiple CNS hemangioblastomas and renal cell carcinoma. He had a germline missense mutation in the VHL gene, c.345C>A (p.His115Gln) (incorrectly reported in the current paper as “c.346C>A” and corrected by the authors to “c.345C>A” via email correspondence). The patient had a negative family history of VHL disease.