PatientID: 5

KindredID: 5

Case: F, 60Y0M, Bulgarian

DiseaseAssertion: VHL

FamilyInfo: Positive family history for VHL - daughter and grandson; no genotype confirmed.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0000107; HP:0005584 (hemangioblastoma; pancreatic cysts; renal cyst; renal cell carcinoma)

CaseHPOFreeText: retinal capillary hemangioma and RCC were operated on. Bilateral renal and pancreatic cysts were also recorded

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: SNP c.870A>G in CCND1 gene (G>G)

GroupID: 44

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: all 3 patients were said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 24

KindredID: D

Case: Sex Unknown, 29Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: The family history of this patient is negative for the disease; one possibility is that she carries a de novo mutation, although the possibility of non-paternity could not be ruled out. Other affected individuals in Family D died at an early age

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0001737; HP:0005584; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cyst, pancreatic cysts, renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: Symptomatic before 29Y, clinically manifested as 2 cerebellar hemangioblastomas, bilateral retinal angiomas, multiple pancreatic & kidney cysts, unilateral RCC, pheochromocytoma, and broad ligament cystadenoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270

SupplementalData: N/A

Variant: p.D121G (c.362A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223200 https://www.ncbi.nlm.nih.gov/clinvar/variation/223200/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D121G (c.362A>G)

MultipleGeneVariants: N/A

PatientID: 16

KindredID: 11

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0030405 (hemangioblastoma, retinal capillary hemangioma, pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

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: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 13Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 3 other members of this family were included in this study and all had the same VHL variant. Patient 3 (Gen 2) presented with bilateral pheochromocytoma and died due to a ruptured aortic aneurysm of Takayasu arteritis. Patient 4 (Gen 2) presented with bilateral pheochromocytoma. Patient 2 (Gen 1) presented with unilateral pheochromocytoma, PNET and died due to metastatic PNET.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0030405 (Pheochromocytoma, Paraganglioma, Pancreatic endocrine tumor)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma. Metastasis found at age 13. Age of onset for pheochromocytoma and paragangliomas is stated as 6, 9 and 13Y but it is not clear which age pertains to which phenotype.

CaseNotHPOs: HP:0005584; HP:0001737; HP:0009711; HP:0010797 (Renal cell carcinoma, Pancreatic cysts, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 20

KindredID: 10

Case: M, 42Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: No relevant family history.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666; HP:0010797 (Pheochromocytoma, Hemangioblastoma)

CaseHPOFreeText: Unilateral pheochromocytoma.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0005584; HP:0030405; HP:0002668 (Retinal capillary hemangioma, Pancreatic cysts, Renal cell carcinoma, Pancreatic endocrine tumor, Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L163F (c.487C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 480772, https://www.ncbi.nlm.nih.gov/clinvar/variation/480772/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L163F (c.487C>T)

MultipleGeneVariants: N/A

PatientID: III-9

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0005584 (hemangioblastoma, abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

GroupID: 509

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to have the c.500G>A germline variant of the VHL gene. Member 11209 presented with mild renal disease (RCC), member 10939 had unknown renal involvement and members 10901 and 10902 had no renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

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: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: III-16 (proband)

KindredID: 1

Case: M, 52Y0M, Iranian

DiseaseAssertion: VHL

FamilyInfo: Familial history was positive for BL-PCC in his son and his daughters, and for retinal hemangioblastoma and bilateral pheochromocytoma in his siblings. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation.

CasePresentingHPOs: HP:0002666; HP:0006880 (Pheochromocytoma; cerebellar hemangioblastoma)

CaseHPOFreeText: Patient had bilateral pheochromocytoma diagnosed at 30Y which had been operated on surgically at 50Y. He was hospitalized at age 50Y also for headache, vertigo, and gait problems for the past 2 months. Brain MRI then showed a huge lobulated hyper-intense lesion measuring 48 by 38 by 28 mm in the right cerebellar hemisphere with significant projection into the fourth ventricle, consistent with hemangioblastoma of reticular pattern.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.

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: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 48Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s daughter had bilateral adrenal pheochromocytoma at 27Y, and was found to have bilateral small lesions suspicious for inactive retinal angiomas upon further investigation. Genetic testing found that the patient’s daughter carried the same NM_000551.3:c.277G>A mutation that the patient was found to carry. The patient’s granddaughter was also found to carry the mutation. The patient's mother had also died at 42Y as a result of a stroke, and the patient’s uncle had died at 57Y as a result of a stroke. There is no genetic information available about them. The other daughter of the patient did not carry the mutation.

CasePresentingHPOs: HP:0006748; HP:0030424; HP:0000107 (Adrenal pheochromocytoma, epididymal cyst, renal cyst)

CaseHPOFreeText: The 48Y male patient presented with a right adrenal pheochromocytoma at 48Y. Further investigation revealed left epididymal cysts and bilateral renal cysts.

CaseNotHPOs: HP:0009713; HP:0009711 (Spinal hemangioblastoma, retinal hemangioblastoma)

CaseNotHPOFreeText: An MRI of the brain and spinal cord showed no signs of hemangioblastomas and examination of the eyes showed no retinal hemangioblastomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93S (c.277G>A)

LegacyVariant: N/A

ClinVarID: 2237, https://www.ncbi.nlm.nih.gov/clinvar/variation/2237/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93S(c.277G>A)

MultipleGeneVariants: N/A

PatientID: 34

KindredID: 34

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0010797 (Retinal capillary hemangioma, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma and RCC.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L249P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Nucleotide deletion (i.e. 746T>C) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.533T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 3

Case: Sex Unknown, 9Y3M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0009711, HP:0009715, HP:0010797, HP:0002666, HP:0005584 (retinal capillary hemangioma, papillary cystadenoma of the epididymis, hemangioblastoma, pheochromocytoma, renal cell carcinoma)

CaseHPOFreeText: At first presentation (age 5Y6M) the patient had a visual acuity of 20/125. The retinal angioma showed an endophytic growth pattern and was located in the temporal disc margin. Before age 5, the patient had experienced epidydimal cystadenoma and hemangioblastoma of the central nervous system. Either at first presentation or on follow-up the patient presented with renal cell carcinoma, pheochromocytoma, and hemangioblastoma of the CNS.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115R (c.344A>G)

LegacyVariant: p.H115R (c.557A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 664415 https://www.ncbi.nlm.nih.gov/clinvar/variation/664415/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: H115R (c.344A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F43

Case: Sex unknown, 27Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives

CasePresentingHPOs: HP:0009711; HP:0009713; HP:0006880; HP:0000107; HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

CaseHPOFreeText: Development of Broad ligament cysts were also observed. Age of onset is 27Y0M.

CaseNotHPOs: HP:0002666; HP:0006770 (pheochromocytoma, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

PatientID: III:5

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 1

Case: Sex Unknown, 59Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

CaseHPOFreeText: 56Y at CNS hemangioblastoma and first ocular angioma (retinal capillary hemangioma, bilateral). Total of 6 ocular angiomas and 1 CNS hemangioblastoma tumors.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: P11

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 2

Case: Sex Unknown, 1Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: One other family member presented with his VHL mutation and was asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 0Y. Age at the end of study: 1Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130I (c.388G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753916, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.388G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V130I (c.388G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 39CE

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 39CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80N (c.239G>A)

LegacyVariant: p.S80N (c.452G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 1070179 https://www.ncbi.nlm.nih.gov/clinvar/variation/1070179/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

PatientID: 40

GroupID/ KindredID: 40

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L178P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 1

GroupID/ KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: p.S65L (c.407C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

GroupID: 161

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

Variant: p.E186K (c.556G>A)

LegacyVariant: c.769G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 161403, https://www.ncbi.nlm.nih.gov/clinvar/variation/161403/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E186K (c.556G>A)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 4

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Three total family members presented with this germline variant in VHL. No phenotypes were reported for patients 6 and 7 of this family.

CohortInfo: A retrospective analysis of case notes of 17 patients was performed for this study. Initially, 23 consecutive patients with VHL disease followed by the Department of Endocrinology at St Bartholomew's Hospital since 1988 were reviewed.

CasePresentingHPOs: HP:0001737; HP:0000077; HP:0002666 (Pancreatic cysts, Abnormality of the kidney, Pheochromocytoma)

CaseHPOFreeText: This patient had solitary cysts, in the tail of the pancreas and the cyst appeared to have features of a benign cyst on MRI. Also reported as having renal lesions as well as pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Reported as: C712T, assumed to be in Legacy reference sequence (AF010238.1) and mapped to c.499C>T according to NM_000551.3 reference sequence.

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: renal cell carcinoma

FamilyInfo: None

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R69C (c.205C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1059402 https://www.ncbi.nlm.nih.gov/clinvar/variation/1059402/

CAID: N/A

gnomAD: N/A

VariantEvidence: germline deletion on chromosome 3 (>35kb, <90kb) resulting in complete loss of VHL gene. Renal cell carcinoma sample from this patient shows a missense somatic mutation R69C(c.205C>T) in the second copy of VHL gene.

MutationType: missense_variant; transition

CivicName: Deletion AND R69C (c.205C>T)

MultipleGeneVariants: Germline, VHL, Gene deletion

PatientID: (sister)

KindredID: 1

Case: F, Age unknown, Chinese

DiseaseAssertion: unknown

FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history as well as a confirmed presence of this same germline mutation in their family: brother and mother

CasePresentingHPOs: N/A

CaseHPOFreeText: Undiscussed in this report. See PMID: 20120764 for detailed information

CaseNotHPOs: N/A

CaseNotHPOFreeText: No clinical manifestations of hereditary syndromes, including MEN2A, MEN2B, VHL, and NF1 were found

CasePreviousTesting: N/A

PreviouslyPublished: 20120764 - contains detailed family and patient information

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: I.3

KindredID: F8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

CasePresentingHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseHPOFreeText: Presented with CNS hemangioblastoma and pheochromocytoma. Tumors detected at ages 24 and 46.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+648T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827583, https://www.ncbi.nlm.nih.gov/clinvar/variation/827583/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transition; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+617C>G

PatientID: None (Proband)

KindredID: ASP (Y156C)

Case: F, 55Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Mutation was absent in a clinically healthy son. Proband of this family presented with an apparently sporadic pheochromocytoma and the Y156C germline mutation of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Presented with an apparently sporadic unilateral pheochromocytoma. VHL phenotype noted as type 2C.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Clinical evaluation of the three patients indicated the absence of other VHL-related tumors.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as Y156C and cDNA change was mapped to c.467A>G.

MutationType: missense_variant;transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

PatientID: IV-42

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-42) appears to have inherited this disease from his mother, along with many of his siblings. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: This member was examined in St. Johns at the Memorial University of Newfoundland. He had pheochromocytoma which was not further described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

PatientID: None

KindredID: 1

Case: M, 77Y0M, ethnicity unknown

DiseaseAssertion: asymptomatic

FamilyInfo: DNA analysis of other close relatives showed that three clinically unaffected first and second degree relatives (aged 17-77 years) were also carriers of a P81S germline mutation, and one with cerebellar hemangioblastomas. See Figure 3 for pedigree.

CasePresentingHPOs: None.

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040; 9829911; 8634692; 17661816 (mentioned as a group)

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: p.P81S (c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81S (c.241C>T)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: F, 70Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient was found to have multiple benign tumours 4 cm in size in her adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHC/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: The patient had LOH of SDHD and VHL as indicated in Table 1.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: Somatic, RET, c. 2307T>G

PatientID: 2

KindredID: 1

Case: F, 5Y0M, Japanese

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father who she got the mutation from presented with adrenal pheochromocytoma, renal neoplasm, hemangioblastoma, and retinal capillary hemangioblastoma. The patient's grandfather died suddenly at age 63 but no autopsy was performed. The grandmother, uncle, and younger sister were tested but found to be genotypically normal.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238Q (c.713G>A)

CaseProblemVariantFreeText: N/A

ClinVar: 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:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: RCC-23

KindredID: 1

Case: Sex and Age unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0006770 (Clear cell renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: F, 18Y, Spanish

DiseaseAssertion: pheochromocytoma

FamilyInfo: Spanish family of 15 members studied, over 2 generations. 6 members had VHL presentations, 1 was a carrier, and 4 others had the mutation, while 2 were not sequenced. This patient’s sister, brother, father, aunt and two cousins all showed positive for the familial mutation.

CasePresentingHPOs: HP:0002666 (adrenal pheochromocytoma)

CaseHPOFreeText: born in 1969, passed in 1987 at 18Y and had left (12cm) and right (14cm) adrenal pheochromocytoma tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238T, C>T

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

VariantEvidence: This mutation was assumed due to the patient’s young age of pheochromocytoma, and family history. Originally, this patient had a suggested clinical diagnosis of MEN2A due to the presence of incidental thyroid C-cell hyperplasia found. However, family screening for medullary thyroid carcinoma (with CEA) failed to detect any abnormalities.

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II:3

KindredID: 1

Case: F, 48Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: Spanish family of 15 members studied, over 2 generations. 6 members had VHL presentations, 1 was a carrier, and 4 others had the mutation, while 2 were not sequenced. This patient’s 2 children presented with the VHL mutation, and her brother and 3 of his children presented with VHL symptoms

CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangiomas)

CaseHPOFreeText: First studied at 43Y, this patient had a right accumulation of pheos at 6cm, and retinal angiomas

CaseNotHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseNotHPOFreeText: Brain MRI and CT-scans were normal.

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238T, C>T

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 23

KindredID: 4

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four members of this family, IDs #22 (8Y, F), #23 (25Y, M), #24 (14Y, M), #25 (12Y, M), were found to have the same variant and pheochromocytoma.

CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Synchronous multifocal pheochromocytoma. 25Y at VHL diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III-2

KindredID: 1

Case: M, 62Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: His mother (II,2) did not carry the mutation. His father (II-1) died age 42 from a cerebellar hemangioblastoma, while his paternal grandparents died at an advanced age and had no known history of VHL manifestations. His brother (III,1) did not harbour the mutation. The patient and his wife (III,3) who did not carry the mutation, had 3 daughters; two with the mutation and one without. Two of his daughters who carried the mutation, aged 28 and 36 (IV-2, IV-3), had a personal history of CNS and retinal hemangioblastomas. Patient IV-2 recently developed a ccRCC and a pheochromocytoma, and patient IV-3 a pancreatic neuroendocrine tumor. Refer to pedigree in Figure 1.

CasePresentingHPOs: HP:0006770, HP:0010797, HP:0009711 (clear cell renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma)

CaseHPOFreeText: The patient died at age 62 of CNS complications.

CaseNotHPOs: HP:0002666, HP:0030405 (pheochromocytoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: No erythrocytosis; the hematocrit, red blood cells count and Epo levels were all normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes supplemental data and figures. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Data.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Figures.pdf

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232 https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

CAID: CA020510 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.598C%3ET

gnomAD: 0.0002016 https://gnomad.broadinstitute.org/variant/3-10191605-C-T

VariantEvidence: The patient was a heterozygous carrier of a single R200W and R161Q mutation (both on the same VHL allele).

MutationType: missense_variant;transition

CivicName:R200W(c.598C>T) and R161Q(c.482G>A)

MultipleGeneVariants: Germline, VHL, c.482G>A (p.Arg161Gln)

GroupID/ KindredID: F18

Case: Sex unknown, 33Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: Noted of familial antecedents with a total of 2 affected family members. (See Table 2)

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0001737 (retinal capillary hemangioma, cerebellar hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: cerebellar HB and pancreatic cysts found with with multiple lesions. Age of onset is 33Y0M.

CaseNotHPOs: HP:0006770; HP:0002666; (clear cell renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F34

Case: Sex unknown, 33Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives.

CasePresentingHPOs: HP:0006770; HP:0009711; HP:0006880; HP:0000107; HP:0001737 (clear cell renal cell carcinoma, retinal capillary hemangioma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

CaseHPOFreeText: Multiple lesions were found with the patient’s retinal and cerebellar hemangioma. Unilateral ccRCC was found. Age of onset is 33Y0M.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: F69

Case: Sex unknown, 27Y0M, Spanish

DiseaseAssertion: pheochromocytoma

FamilyInfo: familial antecedents found of pheochromocytoma

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Bilateral pheo. Age of onset is 27Y0M.

CaseNotHPOs: HP:0006770; HP:0000107; HP:0006880; HP:0001737; HP:0009711 (clear cell renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F26

Case: Sex unknown, 31Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: Noted of familial antecedents of phaeochromocytoma and CNS hemangioblastoma.

CasePresentingHPOs: HP:0009711; HP:0000107 (retinal capillary hemangioma, renal cysts)

CaseHPOFreeText: Age of onset is 31Y0M.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0006880; HP:0001737 (clear cell renal cell carcinoma, pheochromocytoma, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121G (c.362A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223200 https://www.ncbi.nlm.nih.gov/clinvar/variation/223200/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: D121G (c.362A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F61

Case: Sex unknown, 15Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found of clear cell RCC

CasePresentingHPOs: HP:0009711; HP:0002666; HP:0000107 (retinal capillary hemangioma, pheochromocytoma, renal cysts)

CaseHPOFreeText: Unilateral pheo. Age of onset is 15Y0M.

CaseNotHPOs: HP:0006880; HP:0006770; HP:0001737 (cerebellar hemangioblastoma, clear cell renal cell carcinoma, pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162Y (c.485G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223225 https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 23

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had CNS-HB; other phenotype unknown (see table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10567493

SupplementalData: N/A

Variant: p.I151T (c.452T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428803, www.ncbi.nlm.nih.gov/clinvar/variation/428803/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: I151T (c.452T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL11

Case: M, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had LOH found in the BAC array CGH data.

MutationType: missense_variant;transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

PatientID: 8828

KindredID: 1005

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 269.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

PatientID: 6270

KindredID: 279

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 60.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 5 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: paraganglioma, hemangioblastoma, lung metastases and spinal hemangioblastoma but the presenting patient is unclear.Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 18 years later but it is unclear if this pertained to all affected family members.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 4

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 3 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: hemangioblastoma, parathyroid nodule, and esophageal carcinoma but the presenting patient is unclear. Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 25 years later but it is unclear if this pertained to all affected family members. VHL type 2C.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 7

Case: Sex Unknown, 63Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: A first degree relative tested positive for the same VHL mutation (patient B7), they had a cerebellar hemangioblastoma at 30 years old

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D179N (c.535G>A)

LegacyVariant: p.D179N (c.748G>A)

ClinVarID: 419861 (https://www.ncbi.nlm.nih.gov/clinvar/variation/419861/?new_evidence=false)

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191542-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: p.D179N(c.535G>A)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

Variant: p.L118P (c.353T>C)

LegacyVariant: p.L189P (c.566T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428807, https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: Nucleotide deletion (i.e. 566T>C) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.353T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: L118P (c.353T>C)

MultipleGeneVariants: N/A

PatientID: 22

KindredID: 737

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0030405; HP:0002666; HP:0005584 (pancreatic endocrine tumour, pheochromocytoma, renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 29

KindredID: 372

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0030405 (pheochromocytoma, pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 503

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 503 was mentioned (Patient: 7). This patient was found to have a pancreatic endocrine tumour, pheochromocytoma and renal cell carcinoma.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692 https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: IV-7

KindredID: 2

Case: F, 36Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0009713 (Spinal hemangioblastoma)

CaseHPOFreeText: Spinal cord hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: V-3

KindredID: 2

Case: F, Age Unknown, Mexican

DiseaseAssertion: Asymptomatic

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: IV-6 (Proband)

KindredID: 2

Case: F, 23Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: 32

KindredID: 2301

Case: F, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of her family (patient 33) presented with one pathologic pancreatic neuroendocrine tumour and had the same VHL gene mutation.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with two pathologic pancreatic endocrine tumours with metastases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167W (c.712C>T)

CaseProblemVariantFreeText: N/A

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

CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 11

Case: F, 19Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0007850 (retinal vascular proliferation)

CaseHPOFreeText: Retinal vascular proliferation in the patient's eye were associated with a large fibrovascular component and was managed surgically. Presurgical and postsurgical optical coherence tomography in patient 11 demonstrated the fibrovascular complex as a hyperreflective layer that was limited to the vitreoretinal surface. There was traction on the underlying retinal tissue, resulting in thickening and obliteration of the foveal contour. Postsurgically, excision of the complex restored the overall shape of the foveal contour, leaving behind only a small disruption in the outer retinal lamination (corresponding perhaps to the inner segments at the base of the foveal pit) and a small residual macular epiretinal membrane.

CaseNotHPOs: HP:0002011, HP:0001732, HP:0012210 (Morphological central nervous system abnormality, abnormality of the pancreas, abnormal renal morphology)

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: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 6

Case: F, 34Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0002011, HP:0001732, HP:0007850, HP:0012210, HP:0030424 (Morphological central nervous system abnormality, abnormality of the pancreas, retinal vascular proliferation, abnormal renal morphology, epididymal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78D (c.232A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625226 https://www.ncbi.nlm.nih.gov/clinvar/variation/625226/

CAID: CA351749284 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.232A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78D (c.232A>G)

MultipleGeneVariants: N/A

PatientID: 32

KindredID: 32

Case: M, 38Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0005584; HP:0009711 (Renal cell carcinoma, Retinal capillary hemangioma)

CaseHPOFreeText: Multiple pr bilateral retinal hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Phenotypes revised from previous reports (see “PreviouslyPublished” section below for reference).

CaseNotHPOs: HP:0010797 (Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: “Kim, J. H., Cheon, S. H., Oh, C. S., Kim, Y. M. & Park, R. J. Cystic renal cell carcinoma associated with von Hippel–Lindau disease treated by nephron sparing Surgery. Korean J. Urol. 46, 93–95 (2005)” (Reference 9 in the current publication).

SupplementalData: N/A

Variant: p.S139F (c.416C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 216478, https://www.ncbi.nlm.nih.gov/clinvar/variation/216478/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S139F (c.416C>T)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: M, 55Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: Multiple or bilateral CNS hemangioblastoma. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E70K (c.208G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/

CAID: N/A

gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 15

Case: M, 34Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0010797, HP:0005584 (Hemangioblastoma, renal cell carcinoma )

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19949673

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

GroupID/ KindredID: VHL 3

DiseaseAssertion: assumed VHL

GroupSize: 11

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 11 patients with the given mutation belonging to VHL family 3

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts)

GroupHPOFreeText: retinal capillary hemangioma was found in 3 members, hemangioblastomas in 7 members, renal cyst in 7, renal cell carcinoma in 5, and pancreatic cysts in 6

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L89P (c.479T>C)

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: See HaeIII digestion in Fig. 3b

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: None - The family history was negative for hypertension, PHEO or other neuroendocrine tumours. Their parents however, decided not to be tested neither to extend the test to other family members

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Apparently sporadic pheo. He had a history of occipital headache, slightly elevated blood pressure with normal ophthalmological examination for 2 months was found to have a 4-cm-diameter left adrenal mass at MRI, being the abdominal sonography negative. He underwent surgery of the pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D197N (c.589G>A)

LegacyVariant: p.D197N (g.13,278)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756524 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.589G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D197N (c.589G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her youngest sister had bilateral angiomas, liver lesions, and metastatic islet cell cancer. Her second oldest sister had two hypervascular pancreatic head tumours, a complex left renal cyst, and enlarged bilateral ovarian cysts. Her third oldest sister had a pancreatic head tumour and bilateral renal cysts. The oldest sister did not carry the mutation or have any abnormal presentations. The patient's mother was found to harbor the mutation and had retinal angiomas, bilateral adrenal pheochromocytoma, and pancreatic cysts. The patient's maternal grandmother was suspected to have VHL as she developed progressive blindness at age 32 and was completely blind by age 36. She died at age 68 due to an acute hemorrhage into and around a vascular tumour. The patient's maternal aunt died suddenly at age 51 due to a cerebellar hemangioblastoma. One of the aunt's children died at age 25 due to a cerebellar hemangioblastoma and another had bilateral retinal angiomas and multiple pancreatic cysts. Refer to Figure 1 for pedigree.

CasePresentingHPOs: HP:0009711, HP:0006880, HP:0030405, HP:0002896 (retinal capillary hemangioma, cerebellar hemangioblastoma, pancreatic endocrine tumour, neoplasm of the liver)

CaseHPOFreeText: Presented with bilateral retinal angiomas and cerebellar hemangioblastoma at age 29. Three months later presented with abdominal pain which was found to be due to metastatic islet cell cancer. Laparotomy revealed multiple 1 to 2 mm bilobar liver lesions but the primary pancreatic tumour was unresectable because of involvement of the superior mesenteric artery.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.R167Q (c.713G>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: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 19Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: The patient had a son who was asymptomatic but had the VHL gene mutation. The patient's brother (the proband) had the VHL mutation and presented with hypertension, renal cell carcinoma, papillary cystadenoma of the epididymis, renal cyst, and pancreatic cysts. The patient’s father died of renal cell carcinoma at the age of 49. 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:0009713 (Spinal hemangioblastoma)

CaseHPOFreeText: The patient had spinal hemangioblastomas at age 19.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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: 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