PatientID: None

KindredID: 1

Case: M, 40Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: The patient’s father died of renal cell carcinoma at the age of 49, his brother had a spinal hemangioblastoma which was removed at 19 years of age (he was confirmed with this germline mutation) and he had a son who was asymptomatic but was confirmed with this germline mutation. The patient's mother had uterine cancer, the paternal grandmother died at age 92 years of pancreatic cancer, a paternal grandfather died at age 52 years from lung cancer, and the paternal grandfather’s nephew had been diagnosed with a brain tumor. Refer to pedigree at Figure 3.

CasePresentingHPOs: HP:0000822, HP:0005584, HP:0009715, HP:0000107, HP:0001737 (Hypertension, renal cell carcinoma, papillary cystadenoma of the epididymis, renal cyst, pancreatic cysts)

CaseHPOFreeText: His past medical history was significant only for hypertension for three years for which he took atenolol and terazosin. Renal angiography demonstrated multiple vascular lesions involving both kidneys with an angiographic pattern consistent with malignancy. Renal pathology revealed multiple foci of renal cell carcinoma with nine tumors in the right kidney and evidence of micrometastases. The adjacent parenchyma was filled with multiple, dilated cysts. There was evidence of tumor extension into the proximal renal veins and the perinephric fatty tissue.The pathologic findings of the left kidney were similar to the right kidney and demonstrated multiple foci of renal cell carcinoma. In addition, the patient underwent scrotal exploration and local excision of a complex epididymal mass, which was found to be a clear cell papillary cystadenoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Magnetic resonance imaging of the brain and spinal cord, and a thorough ophthalmologic examination were performed; all of which were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86L (c.257C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.P86L (c.470C>T)

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 3

Case: M, 45Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL disease was described for this patient. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0000107; HP:0001737; HP:0000787 (cerebellar hemangioblastoma; spinal hemangioblastoma; renal cyst; pancreatic cysts; nephrolithiasis)

CaseHPOFreeText: At 40Y, Patient 4 was diagnosed with spinal and cerebellar hemangioblastomas, as well as multiple renal and pancreatic cysts. He was diagnosed with VHL disease type 1. At 43Y, renal cysts and stones were discovered. A year later, more spinal hemangioblastomas and renal stones were found. A year later, cerebellar lesions, as well as renal and pancreatic cysts were reported (see table 1).

CaseNotHPOs: HP:0002088; HP:0001392; HP:0005264; HP:0001743 (abnormal lung morphology; abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the lungs, liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

Variant: p.N90del (c.268_270del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524783, https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA645524783

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: N90del (c.268_270del)

MultipleGeneVariants: N/A

PatientID: 27

KindredID: 9

Case: F, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: The proband, patient 27, presented at age 36 with a CNS hemangioblastoma, and renal cell carcinoma and multiple pancreatic cysts and tumors at 40.

CaseNotHPOs: HP:0002666, HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A