In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The V84L (c.250G>C) germline mutation of the VHL gene was found in a 24 yr old VHL patient with pheochromocytoma (index case 141). Parents and siblings were negative for the mutation. No phenotype details are noted for these family members.

53-year-old male presented to the hospital with recurrent chest pain, sweating, palpitation and hypertension. Transthoracic echocardiography revealed a left ventricular enlargement. An abdominal CT scan revealed a tumor in the right adrenal gland, 5.3cm in size. He was hospitalized again due deteriorating symptoms involving a left anterior descending stenosis. He was admitted to the intensive care unit and died of cardiogenic shock. A diagnosis of VHL syndrome was confirmed once genetic analysis revealed a heterozygous V84L(c.250G>C) missense mutation in the patient and his daughter, however his elder son did not possess the mutation. A diagnosis of VHL type 2C was made due to the pheochromocytoma complicated with myocardial damage, myocardial infarction and heart failure.

At age 9, a male caucasian patient was admitted with hypertension and tachicardia. His history included café-au-lait spots since birth, four months of night sweats and three weeks of fevers, bifrontal headaches and fatigue. An MRI scan showed a 3cm left adrenal mass and an MIBG showed increased activity in the left adrenal gland. One month later the patient underwent a successfull adrenalectomy. Four years post-surgery, the patient presented with bitemporal headaches, fatigue and low-grade fevers but both MRI and MIGB are inconclusive. One year later, symptoms worsened, MRI results were negative. At 18Y he later relapsed with another adrenal pheochromocytoma which was resected. DNA analysis showed a germline mutation Val84Leu in VHL. This mutation could correspond to either c.250G>C or c.250G>T. Neither of the parents carried mutations of the VHL gene. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.