PatientID: II-2

KindredID: Family B

Case: F, 20Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Family positive pedigree showing patient’s father with RCC and CNS hemangioblastoma; as well as 2 siblings: brother and sister with CNS/spinal and retinal hemangioblastomas

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

CaseHPOFreeText: born with oculoauriculo-vertebral (Goldenhar) syndrome (has an asymmetrical face, coloboma at the right optic nerve with secondary amblyopia in her right eye, and a VA of hand motion). Her right eye was also treated for a peripheral retinal hemangioblastoma. She suffers from a small CNS hemangioblastoma. She has had surgery for multiple skin tags on the left side of her face, bilateral epibulbar lipodermoids and right eyelid coloboma

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79P (c.236G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351749311 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.236G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R79P (c.236G>C)

MultipleGeneVariants: N/A

GroupID: 1

Case: M, Age unknown, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: Unknown

CaseHPOFreeText: Other manifestations may be present although not matched with individuals so could not deduce.

CaseNotHPOs: HP:0009715 (Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V62Cfs*5 (c.180del)

LegacyVariant: 393 del G

CaseProblemVariantFreeText: N/A

ClinVarID: 182986 https://www.ncbi.nlm.nih.gov/clinvar/variation/182986/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V62Cfs*5 (c.180del)

MultipleGeneVariants: N/A

GroupID: 10

Case: M, Age unknown, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: Unknown

CaseHPOFreeText: Other manifestations may be present although not matched with individuals so could not deduce.

CaseNotHPOs: HP:0009715 (Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E186* (c.556G>T)

LegacyVariant: p.E186* (c.769G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 381602 https://www.ncbi.nlm.nih.gov/clinvar/variation/381602/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E186* (c.556G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 2

Case: M, 11Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0030405 (Pheochromocytoma; pancreatic neuroendocrine tumor)

CaseHPOFreeText: Benign bilateral pheochromocytoma and PNET at age 11

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: F66

Case: Sex unknown, 12Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found of pancreatic cysts

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Multiple lesions on their retinal hemangioblastoma. Age of onset is 12Y0M.

CaseNotHPOs: HP:0006880; HP:0002666; HP:0000107; HP:0001737; HP:0006770 (cerebellar hemangioblastoma, pheochromocytoma, renal cysts, pancreatic cysts, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

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: 11

KindredID: 11

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient was found to have a single benign tumour 9 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 SDHB as indicated in Table 1.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: N/A (son 3)

KindredID: 12

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: His mother and two other brothers presented with the mutation. One brothers was asymptomatic, while the youngest had a paraganglioma lesion; his mother had pheo and paragangliomas

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Nothing was found through screening

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Y156C

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 1

Case: F, 39Y0M, Japanese

DiseaseAssertion: assumed VHL

FamilyInfo: Her older daughter (P1) with cerebellar hemangioblastoma, retinal capillary hemangioma, pancreatic cysts and a hearing impairment, and her younger daughter (P3) with cerebellar hemangioblastoma, spinal cord tumor, retinal capillary hemangioma, pancreatic and renal cysts both had the p.P86L VHL mutation. Her husband did not.

CasePresentingHPOs: HP:0006880; HP:0009711 (Cerebellar hemangioblastoma; retinal capillary hemangioma)

CaseHPOFreeText: At age 39, suffering from retinal angiomas and a cerebellar hemangioblastoma, she underwent surgery for removal of the brain tumor in another hospital. After the operation she suffered from left facial palsy.

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: 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: 13

KindredID: 13

Case: 20Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98N (c.292T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351750883 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y98N (c.292T>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: 11Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.446delC)

CaseProblemVariantFreeText: Paper reports this as a c.446delG mutation, however a C is positioned at c.446

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432421904 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.446del

gnomAD: N/A

VariantEvidence: paper mistake of "c.446 del G" should rather be 446 del C.

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.446delC)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: F, 41Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: Of the patient’s three sons, two carried the mutation; one son presented with unilateral pheochromocytoma at 15Y, and another son presented with bilateral pheochromocytoma at 11Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 41Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238W(c.712C>T)

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

gnomAD: 3:10191506 C / T, http://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: B3

KindredID: 3

Case: Sex Unknown, 41Y11M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient (B3) had two first degree relatives who were positive for the VHL mutation. The first family member had a hemangioblastoma and retinal angioma at 18 years old and the second family member had a renal cyst at 17 years old.

CasePresentingHPOs: HP:0006880; HP:0002666 (cerebellar hemangioblastoma, pheochromocytoma)

CaseHPOFreeText: The patient was diagnosed with the cerebellar hemangioblastoma at the age of 40 and after a follow up 1 year 11 months later was found to have a pheochromocytoma at the age of 41

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167Q (c.713G>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: 5

KindredID: 4

Case: M, 39Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL mutation - Patient and their 4 relatives harbored p.Arg161X mutation - all with the same phenotypes hemangioblastoma, renal cell carcinoma and pancreatic cysts

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

CaseHPOFreeText: With an age of diagnosis of VHL at 39

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patients with clinical manifestations suggestive of VHL or MEN2 were first screened for VHL or RET mutation, respectively. Possible screening of RET, SDHB and SDHD as well

PreviouslyPublished: N/A

SupplementalData: Yes

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo:

CasePresentingHPOs: HP:0002666; HP:0001028 (Pheochromocytoma, Hemangioma)

CaseHPOFreeText: Was diagnosed with bilateral pheochromocytoma resected when she was the age of 18 years. She presented several relapses, the most recent one at the age of 32, when she was also diagnosed with cerebral angioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82G (c.244C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1297059, https://www.ncbi.nlm.nih.gov/clinvar/variation/1297059/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82G (c.244C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 52CA

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 Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 52CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL familywith 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.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: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4942NCI, 4422NCI, 2005F

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 multiple databases, including: the Neuro Olcologie database in Paris, and the National Cancer Institute database, with an unknown number of members belonging to three family IDs: Family ID 4942NCI, 4422NCI, and 2005F. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as 3 VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

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: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>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

GroupID/ KindredID: 26CA

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 Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 26CA. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170F (c.508G>T)

LegacyVariant: p.V170F (c.721G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756193 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.508G>T

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transversion

CivicName: V170F (c.508G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 51F

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 Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 51F. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P192Qfs*10 (c.575delC)

LegacyVariant: FS (c.786delC)

CaseProblemVariantFreeText: NM_000551.3:c.573delC automaps to c.575delC

ClinVarID: N/A

CAID: CA432423729 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.575delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P192fs (c.575delC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 8YO

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 Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 8YO. 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.W88S (c.263G>C)

LegacyVariant: p.W88S (c.476G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2220 https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 139CA

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 Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 139CA. 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.340+5G>C

LegacyVariant: (c.553+5G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 36901 https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant has a large allele frequency and therefore is likely non disease causing (polymorphism). This paper declares this cariant is predicted to compromise the Elongin-binding site either by truncating the protein or by location between codons 157 and 189.

MutationType: splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: F, 62, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her daughter (IV:2) had three children and one was found to carry the mutation. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:3 and III:11). Patient III:3 had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: 25

KindredID: E

Case: Sex Unknown, 32Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: No family history discussed

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

CaseHPOFreeText: Symptomatic by 32Y, clinically manifested as 3 cerebellar hemangioblastomas, pancreatic and renal cyst

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

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: 7

KindredID: B

Case: Sex Unknown, 26Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: 6 members in this family presented with the mutation. 2 were asymptomatic (ages 2 and 7Y). Other family manifestations include: cerebellar, spinal, bulbar, retinal HBs, pancreatic and kidney cysts, and RCC.

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0001737; HP:0000107;H P:0005584 (cerebellar hemangioblastoma, retinal capillary hemangioma, pancreatic cysts, renal cysts, renal cell carcinoma)

CaseHPOFreeText: Patient had 1 cerebellar HB, bilateal retinal angiomas, pancreatic & kidney cysts, RCC

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: C

Case: Sex Unknown, 21Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

CasePresentingHPOs: HP:0009715 (papillary cystadenoma of the epididymis)

CaseHPOFreeText: Patient had epididymal cystadenoma. They however appeared absent of clinical manifestations of VHL disease prior to clinical and imaging scrutiny.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 1

Case: Sex Unknown, 24Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

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: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584 (hemangioblastoma, pheochromocytoma; retinal capillary hemangioma; 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: 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: 1

KindredID: 1

Case: F, 64Y0M, Japanese

DiseaseAssertion: VHL

FamilyInfo: Her father was killed in an accident when she was young. Her older brother died of renal cell carcinoma associated with VHL disease at the age of 58. Her younger sister was also diagnosed with renal cell carcinoma that was associated with VHL disease. No members past the proband had been genetically tested.

CasePresentingHPOs: HP:0006880; HP:0030078; HP:0005584; HP:0001737 (cerebellar hemangioblastoma; lung adenocarcinoma; renal cell carcinoma; pancreatic cysts)

CaseHPOFreeText: of a hemangioblastoma of the cerebellum when she was 37 years old. Her right kidney was resected because of renal cell carcinoma at the age of 59. Concurrently, she received a pancreatojejunostomy for a pancreatic cyst. At the age of 63, radiofrequency ablation was performed for renal cell carcinoma of her left kidney. In the same year, computed tomography screening of the patient’s lungs detected nodules in the right middle lobe and left upper division. A computed tomography–guided needle biopsy of the nodule in the right middle lobe resulted in a diagnosis of adenocarcinoma (Fig 1). We concurrently performed a lobectomy of the patient’s right middle lobe and a partial resection of the left upper division.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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: Loss of heterozygosity (LOH) at the VHL locus was detected in the lung adenocarcinoma. The hepatic adenocarcinoma was found with somatic EGFR mutations and loss of heterozygosity at the VHL locus; authors speculate that dysfunctional pVHL may promote mutations on the EGFR gene.

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

GroupID: 97

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: 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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>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: 213

KindredID: 80

Case: M, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's son and sister were both confirmed to have this VHL mutation. Their son had a retinal angioma at 26 and a pheochromocytoma at 31. Their sister had a pheochromocytoma at 14. Their mother had renal cell carcinoma at 56, however no genotyping information is available for her.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 52.

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

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: 29

KindredID: 10

Case: M, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 21) and his son were both confirmed with this mutation. His son was asymptomatic at the time of assessment.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's son (patient 29) was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0002666, HP:0009711; HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, 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.F76del (c.227_229del)

LegacyVariant: F76del (c.224_226delTCT)

CaseProblemVariantFreeText: The protein coding change for this variant is listed in this paper as p.F76Cfs*138. However the DNA change listed in this paper (c.224_226delTCT) is equivalent to c.227_229delTCT, and results in p.F76del. This variant is entered on CIViC with p.F76del. As a note the latter c. nomenclature is preferred due to the 3' rule.

ClinVarID: N/A

CAID: CA357012; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 41

KindredID: 14

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

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

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.S80Ifs*79 (c.239del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189245; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239del)

MultipleGeneVariants: N/A

PatientID: 233

KindredID: 86

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 229) had a sister (patient 230) who was genetically confirmed with the mutation, and presented with a CNS hemangioblastoma at age 40. The proband's brother 1 (patient 231) was also confirmed with the mutation and had a retinal angioma at 25, and renal cell carcinoma at 54. The proband's brother 2 passed away before they could be diagnosed/ confirmed with the mutation, but they had a CNS hemangioblastoma at 35. Finally, the proband's nephew (son of brother 2) was genetically confirmed with the mutation and presented with renal cell carcinoma at age 30.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband's nephew (son of brother 2) (patient 233) had a renal cell carcinoma at age 30.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732; HP:0009711; HP:0010797 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, Retinal capillary hemangioma, 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.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: 71

KindredID: 25

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband has the same mutation as her son (patient no.72). Her son did not present with hemangioblastoma, multiple pancreatic cysts/tumors, retinal angioma, renal cell carcinoma, or pheochromocytoma, and is apparently asymptomatic.

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

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 28, multiple pancreatic cysts/tumors at age 28, and hemangioblastoma at age 30.

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

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.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182978, https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

PatientID: 136

KindredID: 51

Case: M, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 136) has a mother (patient 137) who presented with a CNS hemangioblastoma at 32, and renal cell carcinoma/ pheochromocytoma at 38. However, no DNA sample was available for his mother's genetic testing.

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

CaseHPOFreeText: The proband (patient 136) presented with multiple pancreatic cysts/tumors at 21, renal cell carcinoma at 23, and a CNS hemangioblastoma at 25.

CaseNotHPOs: HP:0002666; HP:0009711 (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.P146Gfs*14 (c.435_436ins)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131810, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131810

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: P146Gfs*14 (c.435_436insGG)

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL12

Case: M, 25Y0M, 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 two benign pheochromocytomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4

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:0001732 (hemangioblastoma; retinal capillary hemangioma; pancreatic lesion)

GroupHPOFreeText: 2 members had CNS hemangioblastomas, 1 member had retinal angiomas, and 1 had pancreatic cysts or tumors (an abnormality of the pancreas)

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

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74G (c.221T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.V74G (c.434T>G)

ClinVarID: N/A

CAID: CA70042528 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>G)

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

PatientID: 1 (proband)

KindredID: 1

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Recorded family history of VHL disease, with the patient’s mother, grandmother, two uncles and three aunts also suffering from the disease. Additionally, one uncle had succumbed to RCC and five other individuals in the family had succumbed to cerebral hemangioblastomas. No mutation was stated.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0030405 (cerebellar hemangioblastoma; renal cell carcinoma; pancreatic endocrine tumour)

CaseHPOFreeText: At 20Y was admitted to hospital with symptoms of dizziness, unsteadiness and nausea for three weeks, as well as vomiting for one week (cerebellar hemangioblastoma found in MRI); reoccured at 23Y. At 34Y patient had jaundice (multiple RCCs in the kidneys, and a nodule with a rich blood supply in the pancreatic head observed through CT). Numerous cysts were also identified throughout the pancreas (a possible PNET).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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: None

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The four patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize:2

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The two patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117C (c.351G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 8

Case: Sex Unknown, 35Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Diagnosed with VHL at age 15Y. Presented with 6 CNS hemangioblastomas (15Y) and 2 retinal hemangioblastomas (15Y). Age at the end of study: 15Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R107C (c.319C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751195, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.319C%3ET

gnomAD: 0.000004522, https://gnomad.broadinstitute.org/variant/3-10183850-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R107C (c.319C>T)

MultipleGeneVariants: Germline, VHL, c.353T>C (p.L118P)

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: 81

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.506T>C) was found in 1 VHL family with 4 patients.

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

GroupHPOFreeText: 3 patients had retinal angiomas with a mean age of diagnosis of 22Y, and 2 patients had RCCs with a mean age of diagnosis of 28Y.

GroupNotHPOs: HP:0002666; HP:0006880 (pheochromocytoma, cerebellar hemangioblastoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.L169P (c.506T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 428809 https://www.ncbi.nlm.nih.gov/clinvar/variation/428809/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L169P (c.506T>C)

MultipleGeneVariants: N/A

GroupID: 59

Case: 35Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.256C>T) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: patient had cerebellar hemangioblastoma diagnosed at 35Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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: 51

Case: 38Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.193T>C) was found in 1 VHL family with a single patient.

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

CaseHPOFreeText: patient had retinal hemangioblastoma at age 38, and cerebellar hemangioblastoma at age 38.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65P (c.193T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 547829 https://www.ncbi.nlm.nih.gov/clinvar/variation/547829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

GroupID: 27

Case: 45Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0006880; HP:0005584 (cerebellar hemangioblastoma; renal cell carcinoma)

CaseHPOFreeText: patient had cerebellar hemangioblastoma diagnosed at 25Y, and RCC diagnosed at 45Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Q145* (c.433C>T) 

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625249 https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q145* (c.433C>T) 

MultipleGeneVariants: N/A

PatientID: III-20

KindredID: 1

Case: M, 32Y0M, Turkish

DiseaseAssertion: VHL

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient likely inherited this from his father, and passed it onto his son. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: bilateral adrenal pheochromocytoma. He also had capsular invasion of his adrenal masses.

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 38Y0M, German

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo:All patients from the German registry for VHL with PNETs >3 cm diameter with tumours located in the pancreatic body or tail region.

CasePresentingHPOs: HP:0009711, HP:0009713, HP:0006880, HP:0009726, HP:0030405, HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm, pancreatic endocrine tumour, pancreatic cysts)

CaseHPOFreeText: Retinal angiomatosis at age 17, hemangioblastoma of the cervical spinal cord at age 24, cerebellar hemangioblastoma at age 27, left renal tumor at age 36. Pancreatic endocrine tumour and pancreatic cysts at age 38. She had a laparoscopy which found an 8-cm retrogastric cyst, 3.2-cm benign PNET, and a serous cystadenoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q132* (c.394C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 77

KindredID: 77

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797 (hemangioblastoma )

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0001737, HP:0002666, HP:0000107, HP:0006770 (retinal capillary hemangioma, pancreatic cyst, pheochromocytoma, renal cyst, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA348491 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.337C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 242

KindredID: 242

Case: Sex Unknown, 8Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Indication of family history.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0001737, HP:0002666, HP:0006770, HP:0000107, HP:0010797 (retinal capillary hemangioma, pancreatic cyst, pheochromocytoma, clear cell renal cell carcinoma, renal cyst, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

Variant: c.463+1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526679 https://www.ncbi.nlm.nih.gov/clinvar/variation/526679/

CAID: N/A

gnomAD: N/A

VariantEvidence: The variant was found to affect the B-domain and disrupt donor splice site intron 2 and lead to abnormal protein folding. The variant was predicted pathogenic.

MutationType: splice_site_variant

CivicName: c.463+1G>A

MultipleGeneVariants: N/A

PatientID: 86

KindredID: 86

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.L163I (c.487C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756131

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L163I (c.487C>A)

MultipleGeneVariants: N/A

PatientID: 94

KindredID: 94

Case: Sex Unknown, 27Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Carbonic anhydrase 9 (CA9) mRNA level of 26.95 was detected. Membrane CA9 immunostaining was observed.

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

KindredID: 40

GroupID: 22

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 40 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was observed in this kindred.

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.G114C (c.340G>T)

LegacyVariant: p.G185C (c.553G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751376; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114C (c.340G>T)

MultipleGeneVariants: N/A

KindredID: 54

GroupID: 49

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 54 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.R177Dfs*25 (c.528del)

LegacyVariant: p.247FS (c.741delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423454; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.528del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: R177fs (c.528del)

MultipleGeneVariants: N/A

KindredID: 64

GroupID: 26

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 64 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: No additional phenotypic information is listed for this kindred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N131Pfs*3 (c.390_391delTA)

LegacyVariant: p.201FS (c.603delTA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795179

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: N131fs (c.390_391del)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her two sons and her father had the same VHL mutation.

CohortInfo:Three patients with endolymphatic sac tumors were studied.

CasePresentingHPOs: HP:0001737, HP:0002666, HP:0030393, HP:0009713 (pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, spinal hemangioblastoma)

CaseHPOFreeText: She presented with pancreatic cysts and pheochromocytoma at age 32. She experienced headache and dizziness and a temporal bone mass consistent with an ELS tumor was found on brain MR imaging. A preoperative audiogram showed no hearing function and she underwent a left transcochlear approach and resection of the tumor. The pathological diagnosis was consistent with an ELS tumor. She was later found to have a spinal hemangioblastoma that was resected and included in this study.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: The paper describes the mutation as "C-to-A transversion at position −1 on the exon 3 splice acceptor sequence in the VHL gene"

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3509

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.C233R (c.697T>C)

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

GroupID: 3616

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 4 family members recorded with this mutation.

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

GroupHPOFreeText: 2/4 members had retinal angiomas (hemangiomas), and 2/4 had RCC

GroupNotHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V155Cfs*4 (c.462delA)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.225fs (c.675delA)

ClinVarID: 625251 https://www.ncbi.nlm.nih.gov/clinvar/variation/625251/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V155fs (c.462delA)

MultipleGeneVariants: N/A

GroupID: 32

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.L129P (c.386T>C)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 625242 https://www.ncbi.nlm.nih.gov/clinvar/variation/625242/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L129P (c.386T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 2

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 4 members belonging to the same family were recorded with this mutation.

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

GroupHPOFreeText: 1 patient was recorded with RCC, 1 with retinal capillary hemangioma and 3 with CNS hemangioblastoma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: VHL-20

KindredID: 20

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

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

CaseHPOFreeText: Clinical classification: A2.

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

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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: IV-23

KindredID: 1

Case: M, 36Y0M, Chinese

DiseaseAssertion: Renal cyst

FamilyInfo: Eight affected individuals in the patient’s family were retrospectively identified by reviewing medical records and from the recall of relatives. Three had passed away before 40 years of age because of central nervous system hemangioblastoma. Among the 10 living family members that carried the same NM_000551.3:c.326_339dupTCCACAGCTACCGA the patient carried, 3 had renal cysts and 1 had developed renal cell carcinoma, 2 had central nervous system hemangioblastoma, 1 had retinal hemangioblastomas, 1 was diagnosed with glioblastoma, and 5 were asymptomatic.

CasePresentingHPOs: HP:0000107 (Renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0010797; HP:0005584 (Retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Gly114Serfs*50(c.326_339dupTCCACAGCTACCGA)

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2573051018 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051018

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: G114fs (c.326_339dupTCCACAGCTACCGA)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: Unknown

Case: F, 28Y0M, Dutch

DiseaseAssertion: VHL

FamilyInfo: Unknown - study sampled 15 patients from 5 families

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

CaseHPOFreeText: retinal capillary hemangioma of the right eye

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.V241D

CaseProblemVariantFreeText: Variant determined through the assumption of the authors using Latif et al 1993 (AF010238.1) transcript and adding 71bp to the protein sequence.

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: 2

KindredID: 1

Case: F, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: This patient and her unaffected spouse (patient 1) had four children; one died and was affected, two (patient 5 and 7) had both mutations and presented with pheochromocytoma, and one child (patient 6) was unaffected and carried neither mutation. Patient 7 had a child (patient 9) who also carried both mutations and presented with pheochromocytoma. Furthermore, this patient's brother (patient 3) carried both mutations and presented with pheochromocytoma. He had a child with patient (4) who was unaffected. Their child (patient 8) carried both mutations and presented with pheochromocytoma. Patient 8 had two children; one that did not carry the mutation and was unaffected (patient 10) and another that carried both mutations but was disease free (patient 11). See Figure 3 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8772572, 7563486

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P81S (c.241C>T) and L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser)

PatientID: N/A

KindredID: 1

Case: M, 3Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Family history was remarkable for a renal tumor in the paternal grandmother at age 65, treated by nephrectomy in 1998. Furthermore, a maternal uncle had a history of thyroid cancer, and a maternal cousin had a history of breast cancer. The patient’s parents and a 13-year-old half-brother were healthy.

CasePresentingHPOs:HP:0005584, HP:0000790 ( renal cell carcinoma, hematuria)

CaseHPOFreeText: Computed tomographic scan showed a right renal mass. The tumor was impinging on the renal sinus and extended to the renal capsule. The patient underwent a right nephrectomy. In addition, one of five hilar lymph nodes was positive for metastatic disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p. L188V (c.562C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: t(X;1)(p11.2; p34.3)

PatientID: None (proband 12)

KindredID: 12

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Only his mother was mentioned. She was also found with hemangioblastoma at 30Y, however she died before diagnosis; thus no DNA sample available.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: patient had hemangioblastoma of the CNS diagnosed at 31Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E94* (c.280G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 584477 https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E94* (c.280G>T)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 5

Case: M, 46Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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/