PatientID: 8

KindredID: 8

Case: M, 27Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history for VHL.

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

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0002668; HP:0001737; HP:0002666 (retinal capillary hemangioma, renal cell carcinoma, paraganglioma, pancreatic cysts, pheochromocytoma)

CaseHPOFreeText: At 19Y (in 1997), he presented with headaches, ophthalmological examination showed a right retinal hemangioblastoma (treated by laser). 5 years later (age 24Y) he had a right nephrectomy and left nephron-sparing surgery for renal cell carcinoma. Age 27, a palpable mass on the left side of the neck. CT and MRI revealed a 4-cm carotid body tumor (paraganglioma). The patient also has pancreatic cysts. 

CaseNotHPOs: HP:0010797 (hemangioblastoma)

CaseNotHPOFreeText: MRI scan from case presenting headaches showed a normal CNS

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 2-3 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: EXON 2-3 DELETION

MultipleGeneVariants: N/A

PatientID: 291

KindredID: 115

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband, patient 291, presented with a CNS hemangioblastoma at 27, and at 31 presented with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort 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: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

GroupID: 35

DiseaseAssertion: assumed VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 10 of the 573 patients discussed in this paper were found to have the following mutation belonging to 2 families altogether.

GroupPresentingHPOs: HP:0006880; HP:0009711; HP:0005584; HP:0002666 (cerebellar hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma; pheochromocytoma)

GroupHPOFreeText: 8 patients had retinal angiomas diagnosed at a mean age of 27Y, 4 had cerebellar hemangioblastomas diagnosed at a mean age of 31Y, 1 member had RCC diagnosed at 50Y, and one has pheochromocytoma diagnosed at 27Y.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

GroupID: 85

Case: 27Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.538A>G) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCCs diagnosed at 27Y

CaseNotHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma; cerebellar hemangioblastoma; pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.I180V (c.538A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 161401 https://www.ncbi.nlm.nih.gov/clinvar/variation/161401/

CAID: N/A

gnomAD: 0.00001061 https://gnomad.broadinstitute.org/variant/3-10191545-A-G

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: I180V (c.538A>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 33Y0M, Japanese

DiseaseAssertion: VHL

FamilyInfo: Her father and elder brother were also diagnosed with VHLD, with her father having a medical history of two surgical resections for pancreatic NET and associated metastatic recurrence in the liver.

CasePresentingHPOs: HP:0030405, HP:0009713, HP:0005584, HP:0010797 (Pancreatic endocrine tumor, Spinal hemangioblastoma, Renal cell carcinoma, hemangioblastoma)

CaseHPOFreeText: She first developed multiple solid tumors of the pancreas at age 27 and they continued to grow until she was referred to the institute at age 33. She had a pancreatic endocrine tumour at age 14. At age 19, she had hemangiomas of the fourth ventricle and cervical spinal cord and a renal cell carcinoma of the right kidney treated by nephrectomy at 30 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: Immunohistochemical studies revealed that the tumor cells were positive for synaptophysin and chromogranin A.

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 184

KindredID: 71

Case: M, Age 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother (patient 185) was confirmed with the mutation but was asymptomatic at the time of testing. The proband (patient 184) presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

CaseNotHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as 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