PatientID: None

KindredID: 67

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584; HP:0001732 (Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198Gfs*57 (c.592_593del)

LegacyVariant: c.805_806del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795185, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.592_593del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_framshift_variant

CivicName: L198Gfs*57 (c.592_593del)

MultipleGeneVariants: N/A

GroupID: 9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 3 individuals from a single family (ID 9).

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0001732 (Retinal capillary hemangioma, Hemangioblastoma, Abnormality of the pancreas)

GroupHPOFreeText: CNS hemangioblastoma (3/3), retinal angioma (3/3) and pancreatic tumor or cyst (unspecified) (2/3).

GroupNotHPOs: HP:0005584 (Renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.N78T (c.233A>C)

LegacyVariant: c.446A>C

CaseProblemVariantFreeText: N/A

ClinVarID: 223168, https://www.ncbi.nlm.nih.gov/clinvar/variation/223168/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N78T (c.233A>C)

MultipleGeneVariants: N/A

PatientID: 93

KindredID: 93

Case: M, 36Y0M, Chinese (East Asian)

DiseaseAssertion: Pheochromocytoma

FamilyInfo: Positive family history.

CasePresentingHPOs: Pheochromocytoma (HP:0002666)

CaseHPOFreeText: Pheochromocytoma, with a biggest tumor size of 6.5cm. Age of onset at 10Y and diagnosis at 13Y. 36 years later they were confirmed with a genetic mutation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

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: Described as a pathogenic variant, according to the ACMG guidelines at the time of publication.

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 7

Case: F, 62Y0M, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: Patient had family history of VHL disease. Patient’s nephew presented with renal cell carcinoma at 30, patient's sister/brother presented with a hemangioblastoma at age 39 and then retinal capillary hemangioma, renal cell carcinoma, and abnormality of the pancreas at age 57. Patient’s brother presented with retinal hemangioma at age 25 and renal cell carcinoma at age 54. All three of these family members were genetically tested and possessed the same mutation. Patient’s other brother presented with a hemangioblastoma at age 35 but died before diagnosis and genetic testing.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient presented with hemangioblastoma at age 40

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0006770, HP:0001732 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, clear cell renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178R (c.533T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625261, https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L178R (c.533T>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 12

Case: F, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's son was confirmed to have the genetic mutation and presented with pheochromocytoma, renal cell carcinoma, and abnormality of the pancreas.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

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: None

KindredID: 13

Case: Sex Unknown, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's mother had a hemangioblastoma at age 40 but was not genetically confirmed to have the mutation.

CasePresentingHPOs: HP:0005584, HP:0001732, HP:0009711(renal cell carcinoma, abnormality of the pancreas, retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with cysts or tumours of the pancreas, renal cell carcinoma, and retinal angioma at age 34.

CaseNotHPOs: HP:0010797, HP:0002666 (hemangioblastoma, pheochromocytoma)

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

SupplementalData: N/A

Variant:p.V155Dfs*17(c.464_468delTGTAT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2499306942 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306942&fbclid=IwAR1k8AeHEqS_dwb3ClO4W8AWqBs2tf0malEPJ2nbl-bl7ZkgNC3jeWbaDds

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName:V155fs(c.464_468delTGTAT)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: Sex Unknown, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's father had a hemangioblastoma of the central nervous system at age 42. He was deceased before diagnosis could occur.

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

CaseHPOFreeText: The patient presented with hemangioblastoma and renal cell carcinoma at age 29. At age 33, the patient presented with pancreatic cysts or tumours.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0009715 (retinal capillary hemangioma, pheochromocytoma, Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:29330336

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 15

Case: Sex Unknown, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: The patient presented with hemangioblastoma, renal cell carcinoma, and pancreatic cysts or tumours at age 39.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0009715 (retinal capillary hemangioma, pheochromocytoma, Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: M, 13Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. Patient's aunt/uncle was the proband and had the mutation c.349T>G presenting with renal cell carcinoma, retinal angioma, hemangioblastoma, abnormality of the pancreas, and epididymal or ovarian cystadenoma. Many other members of the family had VHL associated phenotypes and three others were confirmed to have this genetic mutation. Additional familial phenotypes can be found in Table 1.

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

CaseHPOFreeText: The patient presented with hemangioblastoma and retinal angioma at age 13.

CaseNotHPOs: HP:0002666, , HP:0005584, HP:0001732, (pheochromocytoma, renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: The patient did not have a cystadenoma of the epididymis.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.W117G (c.349T>G)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 862346 https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117G (c.349T>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: V5PG

Case: Age unknown, sex unknown, Italian

DiseaseAssertion: assumed VHL

FamilyInfo: 2 twin patients belonging to family V5PG were examined. Both with hemangioblastomas and 1 also with retinal hemangioblastomas. Sequencing of patients’ DNA and paternity and monozygosity of the 2 twins was ascertained, revealed a de novo missense mutation.

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

CaseHPOFreeText: N/A

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: 446 (78) A>G (N78S)

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: None (XI)

KindredID: 7

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

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

CaseHPOFreeText: initially thought to be asymptomatic, first screening showed 1 HB; 5 year follow up showed +RC, PC, RCC

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: None (I)

KindredID: 6

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: Total of 6 family members belonging to Family 6 (see Table 2; or follow KindredID 6)

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

CaseHPOFreeText: 1 HB and bilateral RA at first and final screenings

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: None (IV)

KindredID: 1

Case: Sex and Ethnicity unknown; Age <18Y0M

DiseaseAssertion: asymptomatic

FamilyInfo: Total of 4 family members belonging to Family 1 (see Table 2; or follow KindredID 1)

CasePresentingHPOs: None

CaseHPOFreeText: asymptomatic at first and final (5 year follow up) screening

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223166 https://www.ncbi.nlm.nih.gov/clinvar/variation/223166/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: p.F76del

MultipleGeneVariants: N/A

GroupID/ KindredID: 30CE

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 30CE. 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.Q132* (c.394C>T)

LegacyVariant: p.Q132* (c.607C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: Q132* (c.394C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 8BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to family ID: Family 8BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L135* (c.404T>A)

LegacyVariant: p.L135* (c.617T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754021 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T>A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: L135* (c.404T>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 48CE

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 48CE. 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: (c.464-1G>A)

LegacyVariant: Splice (c.677-1G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: II

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: c.553+1G>A

ClinVarID: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: N/A

gnomAD: N/A

VariantEvidence: Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.

MutationType: splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

PatientID: proband (F2-II-11)

KindredID: 2

Case: F, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patients son (F2-III-9) was a 9-year old male patient with a right adrenal pheochromocytoma. The son later presented with a left adrenal pheochromocytoma at 17-years-old. The patients niece (F2-III-4) was a 33 year old female with bilateral pheochromocytoma. The patients brother (F2-II-3) succumbed to hypertensive intracerebral hemorrhage 21 years prior to this study.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: presented with paroxysmal hypertension (180–210/100–120 mmHg), headache, palpitations and hyperhidrosis in 1985 at the age of 18. US scans showed an isolated mass in the right adrenal gland.

CaseNotHPOs: HP:0005584, HP:0000107, HP:0010797 (renal cell carcinoma, renal cyst, hemangioblastoma)

CaseNotHPOFreeText: no other systematic tumors, including CNS hemangioblastomas, renal cysts or renal cell carcinoma, were identified

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: CA020413

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: F1-III-1

KindredID: F1

Case: M, 5Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: This patients father (F1-II-1) was a 31-year old male patient with pheochromocytoma, renal cell carcinoma, and epididymal papillary adenoma. This patients uncle (F1-II-3) was a 30 year-old who presented with multiple right renal masses, epididymal nodules and multiple pancreatic cysts. Histopathological analysis revealed right renal cell carcinoma with hemorrhagic cyst

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: The patient is asymptomatic

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: CA020131

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

KindredID: 152

GroupID: 47

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.152 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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?dataset=gnomad_r2_1

VariantEvidence:

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

KindredID: 136

GroupID: 21

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.136 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R113* (c.337C>T)

LegacyVariant: c.550C>T (p.R184*)

CaseProblemVariantFreeText: N/A

ClinVarID: 220414, https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113* (c.337C>T)

MultipleGeneVariants: N/A

KindredID: 79

GroupID: 51

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 79 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.I251V (c.751A>G)

CaseProblemVariantFreeText: 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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: I180V (c.538A>G)

MultipleGeneVariants: N/A

KindredID: 11

GroupID: 52

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 11 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184R (c.551T>G)

LegacyVariant: p.L255R (c.764T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756355, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.551T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L184R (c.551T>G)

MultipleGeneVariants: N/A

KindredID: 49

GroupID: 31

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 49 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was observed in this kindred indicating VHL disease type 2.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: Pheochromocytoma was observed in this kindred indicating VHL disease type 2.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P154L (c.461C>T)

LegacyVariant: p.P225L (c.674C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 649525, https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P154L (c.461C>T)

MultipleGeneVariants: N/A

PatientID: 161

KindredID: 62

Case: F, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's daughter presented with a CNS hemangioblastoma and multiple pancreatic cysts and tumors at the age of 14.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 28, and a renal cell carcinoma, multiple pancreatic cysts/tumors, and a pheochromocytoma at age 41.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: 195

KindredID: 75

Case: M, 32Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 32.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Renal cell carcinoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, CNS hemangioblastoma)

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

PatientID: 179

KindredID: 70

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 179) had a daughter (patient 180) who was confirmed with the mutation, and present4ed with a retinal angioma and multiple pancreatic cysts/tumors at 17. The proband also has three family members who were unconfirmed with the mutation (passed away before diagnosis): patient 181 (proband's brother) had a CNS hemangioblastoma at 17, patient 182 (proband's father) had a CNS hemangioblastoma at 49, renal cell carcinoma and multiple pancreatic cysts/tumors at 56, and patient 183 (proband's uncle) had a CNS hemangioblastoma at 32 and a retinal angioma at 30.

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

CaseHPOFreeText: The proband presented with a renal cell carcinoma at 44, and multiple pancreatic cysts/tumors at 28.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

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

Variant: p.C162* (c.486C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223226; https://www.ncbi.nlm.nih.gov/clinvar/variation/223226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162* (c.486C>A)

MultipleGeneVariants: N/A

PatientID: 150

KindredID: 55

Case: M, 17Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 150) has a father (patient 151) who was also confirmed with this germline mutation, and presented at 22 with a CNS hemangioblastoma and 28 with renal cell carcinoma. The proband also has a grandmother (patient 153) who presented with a CNS hemangioblastoma at 43, but who passed away before diagnosis/ genetic testing.

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

CaseHPOFreeText: The proband presented at age 14 with a CNS hemangioblastoma, and age 17 with multiple pancretic cysts/tumors.

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

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.I151S (c.452T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223215, https://www.ncbi.nlm.nih.gov/clinvar/variation/223215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: I151S (c.452T>G)

MultipleGeneVariants: N/A

PatientID: 215

KindredID: 80

Case: F, 14Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's brother (the proband) and nephew both had the same mutation. Their brother had a CNS hemangioblastoma at 26. Their nephew had a retinal angioma at 26, and a pheochromocytoma at 31. Their mother had renal cell carcinoma at 56, however no genotyping information is available for her.

CasePresentingHPOs: ; HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 14.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0010797; HP:0009711 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma, 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: 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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 48

KindredID: 15

Case: F, 19Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (oatient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52.

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

CaseHPOFreeText: The proband's niece 2 (patient 48) had a retinal angioma at 18 and a CNS hemangioblastoma at 19.

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

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.S80Tfs*77 (c.239_245del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189246; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239_245del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239_245del)

MultipleGeneVariants: N/A

PatientID: 113

KindredID: 41

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 26, and at age 36 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort 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.H115Tfs*44 (c.343del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421784, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.343delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H115FS (c.343delC)

MultipleGeneVariants: N/A

PatientID: 57

KindredID: 20

Case: F, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had a CNS hemangioblastoma at age 18. Their father (listed in this paper as the proband) presented with a retinal angioma at 32, a CNS hemangioblastoma at 34, and renal cell carcinoma as well as multiple pancreatic cysts/tumors at 38. Their father passed away before genetic testing could be confirmed.

CasePresentingHPOs: HP:0010797 (CNS Hemangioblastoma)

CaseHPOFreeText: The proband had a CNS hemangioblastoma at age 18.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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: 25

KindredID: 1

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 1 was mentioned (Patient: 33). This patient was found to have a pancreatic endocrine tumour, pheochromocytoma and renal cell carcinoma.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

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: 11

KindredID: 63

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 63 was mentioned (Patient: 19). This patient was found to have pheochromocytoma, renal cell carcinoma and pancreatic endocrine tumour.

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.Y175* (c.525C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182974 https://www.ncbi.nlm.nih.gov/clinvar/variation/182974/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y175* (c.525C>G)

MultipleGeneVariants: N/A

PatientID: 34

KindredID: 94

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

PatientID: III-11

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transversion mutation was found and confirmed in 4 patients (II-2, III-2, III-6, III-10, III-11) and 3 carriers (III-3, III-9, III-14). At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. Could be assumed and deduced their genetics due to pedigree showing future linear relations of this mutation all in generation III.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S168T (c.503G>C)

LegacyVariant: p.S168T (c.716G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.503G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: III-10

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transversion mutation was found and confirmed in 4 patients (II-2, III-2, III-6, III-10, III-11) and 3 carriers (III-3, III-9, III-14). At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. Could be assumed and deduced their genetics due to pedigree showing future linear relations of this mutation all in generation III.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S168T (c.503G>C)

LegacyVariant: p.S168T (c.716G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.503G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient had two children with the same genetic mutation. Son presented with bilateral pheochromocytoma (13Y) and endolymphatic sac tumor (19Y). Daughter was asymptomatic.

CasePresentingHPOs: HP:0005584; HP:0002666; HP:0001945; HP:0000790 (Renal cell carcinoma, Pheochromocytoma, Fever, Hematuria)

CaseHPOFreeText: A 48Y man presented with loin pain, pyrexia and haematuria. He was initially thought to have pyelonephritis but a renal ultrasound scan showed a right renal mass. The CT scan and the MRI confirmed the finding of a large right renal mass invading the renal vein and also identified bilateral adrenal masses. hoarse voice due to a mass impinging on the laryngeal nerves. A diagnosis of VHL presenting with a metastatic right RCC and bilateral pheochromocytomas was made. Despite chemotherapy for the metastatic RCC, he died 1 year after diagnosis.

CaseNotHPOs: HP:0000822 (Hypertension)

CaseNotHPOFreeText: He was normotensive at 48Y.

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: 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: 25

KindredID: 4

Case: F, 12Y0M, 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: Multifocal pheochromocytoma. 12Y 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: 18

KindredID: A

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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:0009711; HP:0002668 (Retinal capillary hemangioma, Paraganglioma)

CaseHPOFreeText: Retinal angiomas aged 16Y. 30Y at VHL diagnosis. Abdominal paraganglioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y185* (c.555C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223233, https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y185* (c.555C>G)

MultipleGeneVariants: N/A

PatientID: III-1

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient’s uncle (II-1) was found to harbor the same germline mutation the patient harbored and had bilateral adrenal pheochromocytoma at 14Y. The patient’s aunt (II-2) was found to harbor the same germline mutation the patient harbored and had left adrenal pheochromocytoma at 10Y. The same germline missense mutation was found in the patient’s mother (II-4) who had right adrenal pheochromocytoma. The grandfather was not available for genetic testing because he had died, apparently secondary to a hypertensive crisis. The five other family members which underwent genetic testing did not have the mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F(c.496G>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her family history was concerning for pheochromocytoma and renal cell carcinoma in her father and a paternal aunt, and a paternal grandmother with history of brain tumor. All of these individuals were deceased. No genetic testing had been performed on any of her affected relatives.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: MRI scan ascertained diagnosis of bilateral pheochromocytoma (which preceded by at least 5 years). The pheo and resulting in recurrent episodes of malignant hypertension and intrauterine fetal demise led to the appropriate peripartum diagnosis of VHL syndrome

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: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 16

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 5 family members recorded with this mutation.

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

GroupHPOFreeText: 4 patients were tallied with a retinal capillary hemangiomas, and 4 with cHemangioblastomas. These phenotypes couldn’t be paired as it was not clear with each member.

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: None of the patients were recorded to have RCC

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

GroupID/ KindredID: 8

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This mutation (p.N78S (c.233A>G)) was found in Family No. 8 with 1 member affected. Germline de novo mutations confirmed by analysis of parents’ DNA. Germline mutations (of 233A>G substitution) were not detected in DNA extracted from blood leucocytes of the parents.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

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

GroupID: 11

DiseaseAssertion: VHL

Group size: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, 2 individuals were suspected of VHL disease, but none developed RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: None of the VHL patients presented with retinal capillary hemangioma.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: Chr3(GRCh37): g.10191507G>A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 13

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, 1 individual was suspected of VHL disease, but did not develop RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: This VHL patient did not presented with retinal capillary hemangioma.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10183797T>C

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

GroupID: 9

DiseaseAssertion: VHL

Group size: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, eight individuals were suspected of VHL disease. 5/8 individuals developed RH, while 3/8 did not.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: Five patients presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: p.L159Es*15 (c.473dup)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432423097, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.473dup

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10191480dup

MutationType: duplication; plus_1_frameshift_variant

CivicName: L159Es*15 (c.473dup)

MultipleGeneVariants: N/A

GroupID: 4485

DiseaseAssertion: assumed VHL

GroupSize: 51

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 51 family members recorded with this mutation.

GroupPresentingHPOs: HP:0010797; HP:0005584; HP:0009711; HP:0002666 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pheochromocytoma)

GroupHPOFreeText: 25 of the 51 family members had an angioma (retinal hemangioma), 29 had RCC, 32 members had CNS hemangioblastoma, and 1 had a pheochromocytoma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (confirmed Zbar 1996 type 2 family 4485NCI)

SupplementalData: N/A

Variant: p.L158P (c.473T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L158P (c.686T>C)

ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

GroupID: 3177

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 6 family members recorded with this mutation.

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

GroupHPOFreeText: 4/6 members had a retinal angioma (hemangioma), and 3/6 members had CNS hemangioblastoma

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82_V84del (c.244_252delCGCGTCGTG)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.153delR-V-V (c.457delCGCGTCGTC)

ClinVarID: N/A

CAID: CA658820713 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.244_252delCGCGTCGTG

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: R82_V84del (c.244_252del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4401

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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.S111R (c.333C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S182R (c.546C>G)

ClinVarID: 223187 https://www.ncbi.nlm.nih.gov/clinvar/variation/223187/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S111R (c.333C>G)

MultipleGeneVariants: N/A

GroupID: 2693

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 7 family members recorded with this mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma)

GroupHPOFreeText: 3/7 members had a retinal angioma (hemangioma), 3 had RCC, and 3 members had CNS hemangioblastoma

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly previously published in PMID 9829911 [F76del (c.226_228del) family (ID 183)]; as well as one member in a future publication: PMID: 32179488

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT due to redundancy

LegacyVariant: p.147delF (c.439delTTC)

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3630

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

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.S80I (c.239G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S151I (c.452G>T)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: III:8

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: One of the proband's maternal cousins was a healthy individual that was demonstrated to carry the same mutation, as revealed by Sanger sequencing: III:8, female. A second cousin, a 28 year old male (the proband III:2), was also found to have the same mutation and had a hemangioblastoma. A further five affected members of the family had previously died from VHL syndrome, including III:8's father (II:5), paternal grandfather (I:1), an uncle (II:3) and aunt (II:2) and a sister (III:10). These deceased family members had not previously been tested for mutations in the VHL gene. Pedigree: see Figure 1.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: All members of the family were examined by two experienced surgeons. Diagnoses of VHL syndrome were determined via investigation of medical histories and performance of physical examinations, including a complete neurological examination and brain magnetic resonance imaging (MRI)

CasePreviousTesting: N/A

PreviouslyPublished: NA

SupplementalData: NA

Variant: p.H115Q (c.345C>A)

ClinVar: 496057 https://www.ncbi.nlm.nih.gov/clinvar/variation/496057/

CAID:N/A

gnomAD: N/A

VariantEvidence: RNA extracted from peripheral blood samples obtained from patients in the pedigree and the healthy controls. No significant difference in the expression of pVHL was demonstrated between the mutated and wild type cDNA, as demonstrated by RT-sqPCR analysis.

MutationType: missense_variant;transversion

CivicName: H115Q (c.345C>A)

MultipleGeneVariants: N/A

PatientID: III:4

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: One of the proband's maternal cousins was a healthy individual that was demonstrated to carry the same mutation, as revealed by Sanger sequencing: III:8, female. A second cousin, a 28 year old male (the proband III:2), was also found to have the same mutation and had a hemangioblastoma. A further five affected members of the family had previously died from VHL syndrome, including pateint III:4's father (II:3), paternal grandfather (I:1), an uncle (II:5) and aunt (II:2) and a cousin (III:10). These deceased family members had not previously been tested for mutations in the VHL gene. Pedigree: see Figure 1.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: All members of the family were examined by two experienced surgeons. Diagnoses of VHL syndrome were determined via investigation of medical histories and performance of physical examinations, including a complete neurological examination and brain magnetic resonance imaging (MRI)

CasePreviousTesting: N/A

PreviouslyPublished: NA

SupplementalData: NA

Variant: p.H115Q (c.345C>A)

ClinVar: 496057 https://www.ncbi.nlm.nih.gov/clinvar/variation/496057/

CAID:N/A

gnomAD: N/A

VariantEvidence: RNA extracted from peripheral blood samples obtained from patients in the pedigree and the healthy controls. No significant difference in the expression of pVHL was demonstrated between the mutated and wild type cDNA, as demonstrated by RT-sqPCR analysis.

MutationType: missense_variant;transversion

CivicName: H115Q (c.345C>A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Her child had polycythemia and had two VHL gene mutations; one he obtained from his father and another he obtained from this patient, the mother. The entire family had normal sensitivity of erythroid progenitors to Epo.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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 is heterozygous for the 598C>T mutation.

MutationType: missense_variant;transition

CivicName: R200W (c.598C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 12

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 3 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: 2 members had CNS hemangioblastomas, 1 has retinal angiomas, 1 had RCC, and 1 had a pancreatic abnormality

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No family members appeared to have the above manifestation.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96* (c.286C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Q96* (c.499C>T)

ClinVarID: 428804 https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q96* (c.286C>T)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 9

Case: F, 59Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another individual (patient 16) from the same family was reported but their relationship to patient 15 was not indicated. This individual had VHL disease but the types of tumours they had were not specified.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient has VHL disease with CNS hemangioblstoma. She also had other tumours, but specific types of tumours were not indicated.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have CNS hemangioblastoma or Retinal capillary hemangiomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597, https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 3

Case: M, 7Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: A family pedigree is provided in figure 1. Both the father and sister of patient 7 were found to have the same mutation. His father had retinal, cerebellar and spinal hemangioblastomas, as well as retinal detachment. His 10-year-old sister did not have any known tumours.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have retinal capillary hemangioma or other known tumours.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 2

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: A family pedigree is provided. Patient’s mother and grandmother have the same mutation. Patient’s mother had a retinal capillary hemangioma and lamellar macular hole in the left eye. The grandmother did not have retinal capillary hemangioma, but she had other tumours that were not mentioned.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001737 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have retinal capillary hemangiomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P192L (c.575C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526677, https://www.ncbi.nlm.nih.gov/clinvar/variation/526677/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P192L (c.575C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Gender Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Renal cell carcinoma

FamilyInfo: The paper stated that the patient had family members with the same mutation.

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.V170D(c.509T>A)

LegacyVariant: p.V170D(c.722T>A)

ClinVarID: 625256, http://www.ncbi.nlm.nih.gov/clinvar/variation/625256

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D(c.509T>A)

MultipleGeneVariants: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize: 15 GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: Dutch GroupAgeRange: 16-71

GroupInfo: 15 out of 82 individuals were grouped together based on all having the c.509T>A of the VHL gene. This individual was classified as 2a/b meaning that it included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0002666; HP:0000107; HP:0001737 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Pheochromocytoma, Renal cyst, Pancreatic cysts)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 31087189

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256, https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: Carrier 3 (son to proband 2)

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

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: II:1

KindredID: 1

Case: M, 73Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0002666; HP:0009713 (Pheochromocytoma, Spinal hemangioblastoma)

CaseHPOFreeText: Deceased. Multiple spinal cord hemangioblastomas diagnosed after adrenal tumor resection. Unilateral pheochromocytoma diagnosed at age 73. Diagnosed with VHL type 2A.

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: 1 (case)

KindredID: 1

Case: F, 34Y0M, Ethnicity Unknown

DiseaseAssertion: renal cell carcinoma

FamilyInfo: No family information/ history was given. She was 19 weeks pregnant, however no other mentions of family.

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

CaseHPOFreeText: The patient had bilateral kidney tumors (9.5 and 2.5 cm in maximum diameter). The larger tumor was clear renal cell carcinoma. The smaller contralateral tumor was focally HMB45 positive and had unusual histomorphology, including features resembling clear renal cell carcinoma with features of both t(6;11)- and t(X;17)/ASPL-TFE3 carcinomas

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I147V (c.439A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 371833 https://www.ncbi.nlm.nih.gov/clinvar/variation/371833/

CAID: N/A

gnomAD: 0.00001061 https://gnomad.broadinstitute.org/variant/3-10188296-A-G

VariantEvidence: HMB45-positive renal tumor resembling a t(6;11) carcinoma. There was a detection of translocation t(6;11) (Alpha/TFEB) and translocation t(X;17) (ASPL/TFE3). LOH was observed in the left-sides cRCC tumor.

MutationType: missense_variant;transition

CivicName: I147V (c.439A>G)

MultipleGeneVariants: N/A

GroupID: 14

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: 1 member is said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: the other 2 members are specifically said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N.A

LegacyVariant: 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

GroupID: 9

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: both members are said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.226_228delTTC)

MultipleGeneVariants: N/A

GroupID: 24

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: Written in paper as IVS1+1G>A

LegacyVariant: N/A

ClinVarID: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

GroupID: 37

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.Y156D (c.466T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351756043 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.466T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y156D (c.466T>G)

MultipleGeneVariants: N/A

GroupID: 21

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 members are said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111C (c.331A>T)

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

ClinVarID: 565557 https://www.ncbi.nlm.nih.gov/clinvar/variation/565557/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S111C (c.331A>T)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 6

Case: M, 11Y0M, 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:0009711; HP:0005562 (Retinal capillary hemangioma, Multiple renal cysts)

CaseHPOFreeText: Multiple or bilateral retinal hemangioblastomas. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma)

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: 39

KindredID: 39

Case: F, 24Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family negative for 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:0009711; HP:0010797; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma)

CaseHPOFreeText: CNS and retinal hemangioblastomas. Multiple or bilateral renal cell carcinoma. Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

Variant: p.C162R (c.484T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496067, https://www.ncbi.nlm.nih.gov/clinvar/variation/496067/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: C162R (c.484T>C)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46

Case: M, 48Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history negative for 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:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Multiple or bilateral renal cell carcinoma. Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: “Shin, K. H., Park, K. J., Kim, S. W., Lee, S. H., Lee, S.-E., Jung, H.-W. et al. Germline mutations of VHL gene in Korean von Hippel–Lindau disease patients. J. Korean Cancer 28, 544–554 (1996).” (Reference 19 in current publication).

SupplementalData: N/A

Variant: p.R108Hfs*23 (c.323_324del)

LegacyVariant: N/A

CaseProblemVariantFreeText: cDna and protein (i.e. c.536delGC deletion) do not match reference sequence. “This mutation, which reported in Shin et al., 1996 described as the reference 19 in our manuscript, was also corrected to c.323_324delGC, p.Arg108Hisfs*23 based on transcript NM_000551.3 in the human mutation database as below” (Author Rhee comment).

ClinVarID: N/A

CAID: CA916832609, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA916832609

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_frameshift_variant

CivicName: R108Hfs*23 (c.323_324del)

MultipleGeneVariants: N/A

PatientID: III (granddaughter)

KindredID: F12

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 4 members of this family (I.mother, II.daughter, II.son, III.granddaughter) presented with pheochromocytoma and were found to have the P138= (c.414A>G) germline variant of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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; synonymous_variant

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

PatientID: None (Mother)

KindredID: F5

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G144R (c.430G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 576437, https://www.ncbi.nlm.nih.gov/clinvar/variation/576437/

CAID: N/A

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188287-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G144R (c.430G>A) and c.340+694_340+711dup

MultipleGeneVariants: N/A

PatientID: III-7

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: N/A

CaseHPOFreeText: Deceased.

CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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: IV-7

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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: V-18

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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: 3

KindredID: 3

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Strong family history. His grandfather died of a brain tumor at the age of 45, his cousin brother was operated for a bilateral PCC and his paternal uncle was diagnosed with hemangioblastoma.

CasePresentingHPOs: HP:0006748, HP:0000107, HP:0001737, HP:0010797 (Adrenal pheochromocytoma, renal cyst, pancreatic cysts, hemangioblastoma)

CaseHPOFreeText: Subsequent CECT revealed a posterior fossa fourth ventricle tumor with hydrocephalus. He underwent a suboccupalcraniatectomy with CI laminectomy with biopsy of the tumor along with VP shunt and then was referred to SGPGIMS. He underwent DSA embolization in view of hypervascular tumor and in preparation of excision. He had a hemangioblastoma of the brainstem.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174 https://www.ncbi.nlm.nih.gov/clinvar/variation/223174/

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A