PatientID: IV-13

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4, including this patient, are asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma, pheochromocytoma, retinal capillary hemangioma, Renal cell carcinoma,abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: IV-13

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4, including this patient, are asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma, pheochromocytoma, retinal capillary hemangioma, Renal cell carcinoma,abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: M, 14Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0010797, HP:0000107, HP:0009711, HP:0001737(hemangioblastoma, renal cyst, retinal capillary hemangioma, pancreatic cysts)

CaseHPOFreeText: The patient was found to have a CNS hemangioblastoma, retinal capillary hemangioma, multiple pancreatic cysts and bilateral renal cysts at age 14. MRI of the brain showed a tiny well-enhanced nodule at the cervicomedullary junction with an adjacent prominent vascular structure.

CaseNotHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: M, 14Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0010797, HP:0000107, HP:0009711, HP:0001737(hemangioblastoma, renal cyst, retinal capillary hemangioma, pancreatic cysts)

CaseHPOFreeText: The patient was found to have a CNS hemangioblastoma, retinal capillary hemangioma, multiple pancreatic cysts and bilateral renal cysts at age 14. MRI of the brain showed a tiny well-enhanced nodule at the cervicomedullary junction with an adjacent prominent vascular structure.

CaseNotHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 9 had p.Asn78Ser (c.233A>G) mutation. Three members were affected, and all had retinal capillary hemangioma and CNS hemangioblastoma. Other demographics of the members were not described.

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 9 had p.Asn78Ser (c.233A>G) mutation. Three members were affected, and all had retinal capillary hemangioma and CNS hemangioblastoma. Other demographics of the members were not described.

Between 1985 and 2017, the clinical materials of patients with VHL disease were collected from 3 different families. Peripheral blood was obtained from each patient for genetic analysis. The VHL gene was amplified by PCR and mutations were confirmed by bi-directional sequencing. Of 22 patients from 3 VHL pedigrees, 10 exhibited VHL gene mutations (3 genotypes) at the germline level. The genotypes of each of the three families were p.R161Q (c.482G>A), p.N78S (c.233A>G), and p.R167Q (c.500G>A), respectively. Family 2: Male proband was admitted at 24Y to the Second Affiliated Hospital due to paroxysmal headache, dizziness and palpitation with hyperhidrosis. MRI results revealed a mass at the right adrenal gland, multiple renal tumors and multiple cysts in the pancreas. Resection of the right adrenal tumor and the upper pole of the right kidney were performed. 3 years later, the patient underwent bilateral epididymal nodule excision and postoperative pathology confirmed patient suffered from papillary cystadenoma of the bilateral epididymal head. The proband's brother (at age 27Y) presented with multiple masses in both kidneys, multiple cysts in both kidneys, and pancreas and epididymal nodules. The patient underwent laparoscopic right radical nephrectomy. The postoperative pathology results confirmed the patient suffered from multiple RCC in the right kidney. The brother's daughter (5Y) was noted to be a germline carrier without any symptoms.

Between 1985 and 2017, the clinical materials of patients with VHL disease were collected from 3 different families. Peripheral blood was obtained from each patient for genetic analysis. The VHL gene was amplified by PCR and mutations were confirmed by bi-directional sequencing. Of 22 patients from 3 VHL pedigrees, 10 exhibited VHL gene mutations (3 genotypes) at the germline level. The genotypes of each of the three families were p.R161Q (c.482G>A), p.N78S (c.233A>G), and p.R167Q (c.500G>A), respectively. Family 2: Male proband was admitted at 24Y to the Second Affiliated Hospital due to paroxysmal headache, dizziness and palpitation with hyperhidrosis. MRI results revealed a mass at the right adrenal gland, multiple renal tumors and multiple cysts in the pancreas. Resection of the right adrenal tumor and the upper pole of the right kidney were performed. 3 years later, the patient underwent bilateral epididymal nodule excision and postoperative pathology confirmed patient suffered from papillary cystadenoma of the bilateral epididymal head. The proband's brother (at age 27Y) presented with multiple masses in both kidneys, multiple cysts in both kidneys, and pancreas and epididymal nodules. The patient underwent laparoscopic right radical nephrectomy. The postoperative pathology results confirmed the patient suffered from multiple RCC in the right kidney. The brother's daughter (5Y) was noted to be a germline carrier without any symptoms.

Of 246 patients affected with von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene were determined from sequencing peripheral blood using PCR, SSCP (single-strand conformation polymorphism), and Southern Blotting. Family 4578 was found with c.233A>G mutation in the VHL gene (legacy notation c.446A>G converted to NM_000551.3). It should be noted that the paper describes the amino acid change to be Asp to Ser but, there is no Asp at position 233. This is assumed to be a mistake, with the correct amino acid change being Asn to Ser. 4/8 had pheochromocytoma, 7/8 had renal cell carcinoma, 5/8 had CNS hemangioblastoma, 3/8 had retinal angiomas and 2/8 had cysts.

Of 246 patients affected with von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene were determined from sequencing peripheral blood using PCR, SSCP (single-strand conformation polymorphism), and Southern Blotting. Family 4578 was found with c.233A>G mutation in the VHL gene (legacy notation c.446A>G converted to NM_000551.3). It should be noted that the paper describes the amino acid change to be Asp to Ser but, there is no Asp at position 233. This is assumed to be a mistake, with the correct amino acid change being Asn to Ser. 4/8 had pheochromocytoma, 7/8 had renal cell carcinoma, 5/8 had CNS hemangioblastoma, 3/8 had retinal angiomas and 2/8 had cysts.

PatientID: 2b

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: An unspecified relative (proband - 2a) had the same mutation with renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, pancreatic cysts and pancreatic endocrine tumors.

CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0002668; HP:0030405 (renal cell carcinoma; hemangioblastoma; retinal capillary hemangioma; pancreatic cyst; pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 2b

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: An unspecified relative (proband - 2a) had the same mutation with renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, pancreatic cysts and pancreatic endocrine tumors.

CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0002668; HP:0030405 (renal cell carcinoma; hemangioblastoma; retinal capillary hemangioma; pancreatic cyst; pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A