PatientID: 10

KindredID: 10

Case: 39Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Recorded as a familial tumor; one other family info present (Patient ID: 9) who is a 47 year old patient with an abdominal paraganglioma

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Unilateral pheochromocytoma reported with an age at diagnosis of 39 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164H (c.492G>C)

CaseProblemVariantFreeText: Paper stated this as c.491G>C; p.Q164H. cDNA position of 492 is most likely correct and matches up. Error by authors to say c.491.

LegacyVariant: N/A

ClinVarID: 618485 https://www.ncbi.nlm.nih.gov/clinvar/variation/618485/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191499-G-C

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q164H (c.492G>C)

MultipleGeneVariants: N/A

PatientID: P16

KindredID: P16

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: N/A

CohortInfo: Tumour samples and paired peripheral blood samples were obtained from 39 patients, consisting of 31 PCs, seven extra adrenal PGLs and one metastasis from a malignant PC previously presenting with a PC.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had a benign pheochromocytoma measuring 50 mm at age 39.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: The tumour tested positive for SDHA and SHB IHC.

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: None (Cousin 2)

KindredID: G

Case: Sex Unknown, 38Y0M, Hungarian

DiseaseAssertion: Assumed VHL

FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, Retinal capillary hemangioma, Pheochromocytoma)

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 38, pheochromocytoma at age 39 and retinal hemangioblastoma at age 29. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as S80I and cDNA change was mapped to c.239G>T.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 21 (Aunt)

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. ID 35 was asymptomatic. IDs 1 (proband), 28, 2, 6, 17 and 19 all presented with pheochromocytoma. ID 5 presented with CNS hemangioblastoma, retinal angioma and renal cyst OR tumor (not specified).

CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 39 and retinal angioma at age 41.

CaseNotHPOs: HP:0005584; HP:0001732; HP:0000077; HP:0010797 (Renal cell carcinoma, Abnormality of the pancreas, Abnormality of the kidney, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.S65A (c.193T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223160, https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 3/4 of her sons also carried the mutation, one of which presented with a paraganglioma.

CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.

CasePresentingHPOs: HP:0002668; HP:0006748; HP:0002886 (paraganglioma, adrenal pheochromocytoma, vagal paraganglioma)

CaseHPOFreeText: At 39Y (in 1993), she presented with recent onset of hypertension and was diagnosed with a right pheochromocytoma. (At age 36, a suspected left pheochromocytoma was noted by CT and confirmed at age 39 by [123I]MIBG scintigraphy). This imaging showed in addition an uptake located in the neck. MRI confirmed a left adrenal tumor and a left 2-cm vagal paraganglioma that was removed and confirmed histopathologically.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No other tumor of the VHL spectrum was discovered. 

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y156C (c.467A>G)

LegacyVariant: p.Y156C

CaseProblemVariantFreeText: The publication only provides the p., the mutation was able to be deduced to p.Y156C (c.467A>G)

ClinVarID: 43600 https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

PatientID: 186

KindredID: 72

Case: F, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 72, has multiple family members with the same mutation. Her father (patient 73) had a CNS hemangioblastoma at 65, renal cell carcinioma at 54, and multiple pancreatic cysts/tumors at 67. Her sister 2 (second sister) had multiple pancreatic cysts/tumors at 36, and a CNS hemangioblastoma at 39. Her sister 3 had multiple pancreatic cysts/tumors at 32, and a retinal angioma at 34. The proband's sister 1 had a CNS hemangioblastoma at 22, but passed away before they could be diagnosed/ confirmed with the mutation.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001732; HP:0001737; HP:0002666 (Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts, Pheochromocytoma)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 37, and a pheochromocytoma at 39.

CaseNotHPOs: HP:0009711 (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).

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

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A