PatientID: III:4

KindredID: 1

Case: M, 56Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

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

CaseHPOFreeText: patent had a combination of cerebellar HB and bilateral pheo, age of onset at 38Y, and operated on the same year

CaseNotHPOs: HP:0006880; HP:0002666; HP:0030405; HP:0001737; HP:0000107; HP:0002668 (pancreatic endocrine tumor, pancreatic cysts, renal cysts, paraganglioma)

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: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: IV:8

KindredID: 1

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

CasePresentingHPOs: N/A

CaseHPOFreeText: unknown phenotype, however they were said to be affected

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?dataset=gnomad_r2_1

VariantEvidence: Death before genetic diagnostic, however presumed by authors due to extensive family history (See pedigree).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: F, 30Y0M, Vietnamese

DiseaseAssertion: VHL

FamilyInfo: None - The diagnosis of VHL had not been established in her parents or her relatives, who lived in Vietnam without further evaluation.

CasePresentingHPOs: HP:0009711; HP:0001737 (retinal capillary hemangioma; pancreatic cysts)

CaseHPOFreeText: At 28Y presented with multiple retinal capillary hemangioma (complicated tractional retinal detachment and multiple large angiomas) and multiple pancreatic cysts. Underwent PPV combined with relaxing retinectomy.

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

GroupID: 47

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have the c.712C>T (R167W) germline variant of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: Number of family affected members is not specified.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151 and/or 8956040

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: 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: 202

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have the c.712C>T (R167W) germline variant of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: Number of family affected members is not specified.

GroupNotHPOs: N/A

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

Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients. All patients had VHL germline mutations. Age is at the time of surgery. Patients #2 (female) and #12 (male) were found with this germline VHL mutation and pancreatic endocrine tumours. The last known age of the patients was 28Y, and 43Y respectively. Other phenotypes and demographics were unknown. ACMG PP4

PatientID: 12

KindredID: 12

Case: M, 43Y0M, 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.R167W (c.499C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 10b

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was positive with 3 other members of unknown relation (10a, 10c, 10d) presenting with the mutation, with various phenotypes, however one member being asymptomatic as of age 3Y.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711; HP:0030405 (Pheochromocytoma; Paraganglioma; Retinal capillary hemangioma; Pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.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: 10a

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was positive with 3 other members of unknown relation (10b, 10c, 10d) presenting with the mutation, with various phenotypes, however one member being asymptomatic as of age 3Y.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0010797; HP:0009711; HP:0030405 (Pheochromocytoma; Paraganglioma; Hemangioblastoma; Retinal capillary hemangioma; Pancreatic endocrine tumor)

CaseHPOFreeText: Patient had pheochromocytoma, paraganglioma, retinal and CNS HB, pancreatic endocrine tumor, along with liver metastasis

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

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: A-V6

KindredID: A-V6

Case: M, 30Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: 2 affected individuals (twin brothers) in this family but no further details provided. Twin brother of proband died of VHL.

CasePresentingHPOs: HP:0002666; HP:0006880 (Pheochromocytoma, Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar hemangioblastomas and bilateral pheochromocytoma. Diagnosed with VHL type 2.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

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: Variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected to c.499C>T. This assumption was made due to later publications referencing this mutation and paper. Variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected due to future publications' reference to this paper regarding this patient and mutation as c.499C>T

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 25

KindredID: 18

Case: Sex Unknown, 35Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405; HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient developed PPGL at 26Y of age, and a PNET at 35Y. They also presented with a CNS HB

CaseNotHPOs: HP:0005584; HP:0001737; HP:0009711; HP:0000107 (renal cell carcinoma, pancreatic cyst, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

This report studied the prevalence of germline variants in Japanese PPGL patients. Of the 370 PPGL original Japanese probands, this cohort consisted of 15 patients with pheochromocytoma and/or paragangliomas with germline VHL varaints. Blood samples were used to examine 7 genes: MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET, using Sanger sequencing. Of these 15 VHL patients: 10 had bilateral PCC, 4 had PCC with abdominal/thoracic PGL, and one had metastatic PPGL. The variant R167W (c.499C>T) was one of the 15 found in a patient with PPGL. Their family history or further manifestations were not detailed.

This paper analyzed the VHL gene of 21 patients who had clinical a clinical diagnosis of VHL, familial pheochromocytoma, or sporadic pheochromocytoma. 7 patients were from 3 families, while the remaining 14 were unrelated. Mutations were detected by realtime quantitative PCR (RQ-PCR) assays using peripheral venous blood. The mutation (c.499C>T) was found in 1 individual (33Y, M), without family history, who presented with pheochromocytoma, hypertension and diabetes mellitus. This case was also later presented in PMID: 24735130 (Pai et al, 2014). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 4 VHL type 2 families of 51 individuals altogether (family IDs 2338, 3490, 4477, 4405). 36 of 51 individuals had retinal hemangioblastomas, 17 had CNS hemangioblastomas, 16 with renal cell carcinoma, and 36 with pheochromocytomas. This mutation was also detected in an additional family with 1 single member, with retinal angiomas (family ID 3699). Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

PatientID: IV-34

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-34) appears to have inherited this disease from her mother, along with many of her siblings. See Fig. 1 for family pedigree.

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

CaseHPOFreeText: This member was examined in St. Johns at the Memorial University of Newfoundland. She had pheochromocytoma and retinal angiomas which were not further described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III-4

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This female (III-4) appears to have inherited this disease from her mother and has passed it onto to her daughter thereafter. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

Case: F, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This woman (II-1) appears to have inherited this disease from her father, and passed it onto her 6 children, and many kin thereafter. See Fig. 1 for family pedigree.

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

CaseHPOFreeText: Described as “probable” cerebellar hemangioblastoma and “probable” retinal angioma. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III-1

KindredID: 1

Case: M, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This male (III-1) appears to have inherited this disease from his mother and passed it onto his kin thereafter. See Fig. 1 for family pedigree.

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

CaseHPOFreeText: Patient had cerebellar hemangioblastoma, along with retinal hemangiomas described as “probable”. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: IV-42

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: I-2

KindredID: 1

Case: M, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This male (I-2) appears to be the furthest traced relative with the presumed mutation, passing on to 3 of his 4 offspring, and dozens of kin thereafter. See Fig 1 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: Affected, although details are unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: IV-23

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-23) appears to have inherited this disease from her father. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This member had retinal angiomas which were not further described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: IV-38

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 44

KindredID: 44

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0000107 (Retinal capillary hemangioma, Renal cyst)

CaseHPOFreeText: Retinal hemangioblastoma and renal cystic lesion.

CaseNotHPOs: HP:0002666; HP:0010797; HP:0006770; HP:0001732 (Pheochromocytoma, Hemangioblastoma, Clear cell renal cell carcinoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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: 1 (Proband)

KindredID: 10

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 2 members of this family presented with the c.712C>T/c.499C>T germline variant of the VHL gene. ID 3 presente with CNS hemangioblastoma, retinal angioma and renal cell carcinoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000077; HP:0002666; HP:0001732; HP:0010797; HP:0005584; HP:0009711 (Abnormality of the kidney, Pheochromocytoma, Abnormality of the pancreas, Hemangioblastoma, Renal cell carcinoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 125 (Second cousin)

KindredID: 18

Case: F, 52Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with retinal angioma (19Y). Age of diagnosis of pheochromocytoma and renal cell carcinoma is unknown.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

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: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

Screening of 3 patients affected with familial PC for mutations in the RET proto-oncogene (mutations related to MEN 2 syndrome) and the VHL tumor suppressor gene (mutations related to VHL disease) with the use of PCR, SSCP, heteroduplex analysis, and direct sequencing, revealed missense VHL gene mutations. Please note that there was no clinical diagnosis of VHL disease. This missense mutation c.499C>T was found in a Polish family with 3 siblings (two male siblings and their mother) with no evidence of RET; the older brother presented with unilateral pheochromocytoma at 15Y, the younger brother presented with bilateral pheochromocytoma at 11Y, and the mother presented with bilateral pheochromocytoma at 41Y. Additional phenotypic information was not provided. Please note that the paper states the mutation as c.712C>T because it uses a legacy reference sequence.

PatientID: None

KindredID: 386

Case: M, 15Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: One of the patient’s brothers carried the mutation and presented with bilateral pheochromocytoma at 11Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with unilateral pheochromocytoma at 15Y.

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: None

KindredID: 386

Case: M, 11Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: One of the patient’s brothers carried the mutation and presented with unilateral pheochromocytoma at 15Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.

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: 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

GroupID: 24A

DiseaseAssertion: VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 VHL patients with the given VHL mutation and manifestation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

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: 3

KindredID: 3

Case: 31Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs:  HP:0010797; HP:0005584; HP:0002666 (hemangioblastoma, renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: CNS hemangioblastoma first presenting at 24Y, RCC and pheos at 31Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

The proband (II/3), of italian descent, was found to have the c.499C>T change (referred to in the paper by 8702C->T due to a difference in transcript sequence) causing R167W of the VHL gene. This variant was detected using direct sequencing of PCR products obtained from genomic DNA extracted from the patients peripheral blood leukocytes using the DNA extractor BIO ROBOT EZ 1 (Qiagen). The c.499C>T change was detected in the exon 3 of VHL gene. He had retina angioma with renal carcinoma. His daughter (III/3) also had the mutation and was symptomatic but specific phenotypes were not specified. His son (III/4) was asymptomatic, but it is unclear if he was tested or not for the genetic variant. His father (I/1), had the mutation and presented with a haemangioblastoma. His brother (II/2), also had the mutation and presented with renal carcinoma, central nervous system haemangioblastoma, pheochromacytoma and pancreatic cysts. ACMG evidence codes: 'PP1' since we have cosegregation with the disease in multiple affected family members, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

GroupID: 37

DiseaseAssertion: hemangioblastoma

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 out of the 81 patients listed in this hemangioblastoma cohort were found with this c.499C>T mutation. Any relation is unknown.

GroupPresentingHPOs: HP:0010797 (hemangioblastoma)

GroupHPOFreeText: all patients had hemangioblastoma of the CNS; One patient was said to be found with a primary asymptomatic tumor. Other phenotypes are unknown.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167W (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

A case report of a woman presenting with bilateral adrenal pheochromocytoma and  multiple pancreatic massess (paraganglioma) at 18 years of age is presented. Molecular analysis on peripheral leukocytes confirmed the presence of the above mutation (c.499C>T). Additional clinical manifestations in this patient include retinal and cerebellar hemangioblastomas (at 19Y and 22Y), and a neuroendocrine tumour (at 24Y). Family history shows 3 additional family members who likely have VHL, but have not been genetically tested. Clinical manifestations in these individuals included: pheochromocytoma, pancreatic cysts, and paraganglioma. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' because the patients' phenotype or family history are highly specific for a disease with single genetic etiology.

Through PCR purification and Sanger sequencing of peripheral blood (using an alcohol precipitation method), 121 consecutive, unrelated, index PCC/PGL patients underwent genetic testing for five PCC/PGL susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) and were evaluated for clinical diagnosis of neurofibromatosis type1. Three unrelated probands were genetically confirmed with a familial mutation at c.499C>T of the VHL gene. The first was an 11 year old male who presented with bilateral pheochromocytoma and retinal capillary hemangioma. The second was an 11 year old male who presented with bilateral pheochromocytoma and PNETs. The third was an 18 year old female who presented with bilateral pheochromocytoma and sympathetic paraganglioma, CNS hemangioblastoma and PNETs. Family histories are unknown but positive.

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

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renalcell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There was 1 patient reported with c.499C>T (p.R167W). This member presented with retinal hemangiomas. No family information was provided.

GroupID: 23

DiseaseAssertion: VHL

GroupSize:3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family presented with the c.499C>T germline variant of the VHL gene. Member 1037 had no renal involvement. Members 1035 and 1036 had moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 15 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously reported individuals/families could alternatively correspond to family 1 or 50.

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

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

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.R167W (c.499C>T) germline variant of the VHL gene was detected in multiple families. Family 1: Members 296, 419, 295 and 414 had no renal involvement. Members 427, 318, 403 and 406 had unknown renal involvement. Members 402, 322, 403 and 1 had mild renal disease (RCC). Members 401 and 404 had moderate renal disease (RCC). Family 23: Member 1037 had no renal involvement. Members 1035 and 1036 had moderate renal disease (RCC). Family 50: Member 6338 had no renal involvement. Members 6340 and 6339 had mild renal disease. The paper states that these families are previously reported in PMID 12202531 and/or 9829912.

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Three unrelated probands were genetically confirmed with a germline missense mutation at c.499C>T of the VHL gene. Patients 42 and 44, 10Y and 30Y males respectively, both presented with multiple and/or bilateral pheochromocytoma and CNS hemangioblastomas. Patient 43, 30Y male, presented with multiple and/or bilateral pheochromocytoma and retinal hemangioblastoma. Patients 42 and 43 had a family history negative for VHL disease while patient 44 had a positive family history of VHL disease. Patient 43s phenotypes were revised from a previous report (PMID 19949673). Patient 44 was previously reported in PMID 16142346 as well as Kim et al., 2005 (reference 15 in the current paper). All of these patients were diagnosed with VHL Type 2A.

During the period from 2009 to 2012, 39 families with VHL disease were diagnosed with hereditary VHL disease at Peking University First Hospital Department of Urology were described as part of a broader study examining telomere length and anticipation. In these families, 19 families had two or more than two patients in two or more than two generations, including one family with obscure onset age. Therefore, a total of 57 patients with VHL disease from 18 families were enrolled in this study. Using peripheral blood and southern blotting, DNA sequencing was completed on the following patients. Family 5 involved four members with a c.499C>T change leading to a p.Arg167Trp protein change. The first member, the father, presented with renal cell carcinoma at 63. His 3 daughters also presented. The first daughter presented with hemangioblastoma, renal cell carcinoma, ovarian cyst, and pancreatic cysts at 37, as well as pheochromocytoma at 39. The second daughter presented with pancreatic cysts at 36 and hemangioblastoma at 38. The third presented with retinal capillary hemangioma at 34. The first born son did not present with any symptoms nor the mutation. ACMG Evidence Code: 'PP4' because the patients' phenotypes and family histories are highly specific for VHL disease.

Case studies of three families affected by VHL and their children were described. The legacy mutation C712T in VHL was found in three members of family 1. The father was 48Y when he was found to have renal cell carcinoma and bilateral pheochromocytoma after initially presenting with loin pain, pyrexia and haematuria. He died one year after diagnosis despite chemotherapy treatments. His son was diagnosed with and treated for bilateral pheochromocytoma at 13Y and endolymphatic sac tumors at 19Y after noting tinnitus, increasing hearing difficulties in his left ear since the age of 16. The son had a sister who tested positive for the mutation and appears to be asymptomatic. It is unclear whether the mother and the second son were negative for the mutation or were not tested.

GroupID: 28

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French, German, and British

GroupAgeRange: N/A

GroupInfo: 3 registrants from were grouped in this study via the mutation of c.499C>T

GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

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

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.499C>T), which was found in 3 individuals each from France, UK, or Germany.

A 25 year-old female patient presented with a 2-year history of progressive intermittent headaches, hot flushes, diaphoresis and hypertension. The patient is a non-smoker, non-drinker, with no comorbidities, no recreational drug use or any family history of endocrinopathies, pheochromocytomas or familial syndromes. She denied current or past symptoms of episodic or sustained tachycardia, palpations, dyspnoea, abdominal pain, fatigue or weight loss. A renal Doppler ultrasound ruled out renal artery stenosis, but located a unilateral left adrenal massAn MRI with gadolinium contrast revealed left adrenal mass and detected a smaller right-side adrenal mass and neuroendochrine tumors (confirmed by testing for chromogranin A). The largest pancreatic mass was medial to the uncinate process (3.7×3.0×5.6 cm) and was solid with areas of necrosis while the other pancreatic masses were significantly smaller, cystic, well defined and uniform in character and were in the body and tail of the pancreas. An MIBG whole-body scan confirmed bilateral functional phaeochromocytomas. The patient was suspected for VHL disease which was confirmed by genetic testing that found the R167W (missense) mutation of the VHL gene which had been previously reported in a kindred from Newfoundland. Genes CDC73, CDKN1B, MAX, MEN1, PRKAR1A, PTEN, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and TP53 were found not to be pathogenic. Further imaging found multiple lumbar and thoracic hemangioblastomas.

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

GroupID: 6104

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Each group represents a family.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)

GroupHPOFreeText: 2/5 members with pheochromocytoma, 3/5 members with CNS hemangioblastoma, 1/5 members with retinal angioma, 1/5 members with cysts, 1/5 with renal carcinoma. Diagnosed as a VHL Type 2B family.

GroupNotHPOs: N/A

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: Variant reported as 712, C to T (Arg to Trp), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.499C>T, p.Arg167Trp (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 4

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: F, 18Y, Spanish

DiseaseAssertion: pheochromocytoma

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

CasePresentingHPOs: HP:0002666 (adrenal pheochromocytoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238T, C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II:3

KindredID: 1

Case: F, 48Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

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

CaseNotHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseNotHPOFreeText: Brain MRI and CT-scans were normal.

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238T, C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 23

KindredID: 4

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: F34

Case: Sex unknown, 33Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

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

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 22

KindredID: 737

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 32

KindredID: 2301

Case: F, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

74 patients (38 males, 36 females; 24 with prior sequencing data) with pheochromoctyoma were first analyzed by denaturing high performance liquid chromatography (dHPLC). PCR of all exons of VHL was performed on leukocyte DNA extracted from stored blood samples, and those showing variance were sequenced. In addition, 35 positive controls were used to confirm this method. This patient was a positive control who has been previously sequenced (not referenced). One patient was found with the R167W (c.499C>T) VHL mutation. No family history was mentioned or clearly stated of their phenotypes.

Pathogenic variants from 10,389 individuals across 33 cancer types were examined from The Cancer Genome Atlas (TCGA) cohort. 12 of these individuals had a germline mutation in the VHL gene. The R167W (c.499C>T) missense VHL mutation was found in two individuals, a white 67Y0M female diagnosed with clear cell renal cell carcinoma, as well as a white 19Y0M female diagnosed with pheochromocytoma. No family information was provided.

A 64 year old female was found to have a germline VHL missense mutation (Arg167Trp). The paper does not provide any information about nucleotide change. The patient presented with a large suprasellar hemangioblastoma, and had a documented past history of severe VHL disease, with bilateral ccRCC, bilateral pheochromocytomas, pancreatic cysts, retinal hemangioblastomas, and multiple CNS hemangioblastomas. No information about patient family history was provided. Neurological exam was significant for Romberg sign and mild dysmetria of bilateral upper extremities. A visual field test of the left eye revealed new onset inferior temporal quadrantanopsia. MRI confirmed a suprasellar hemangioblastoma within the circle of Willis with increased optic tract edema and compression of the optic chiasm. Left eye extraocular movements and pupillary reaction intact. The patient was treated with octoreotide for 9 months, leading to resultant clinical stability and decreased tumor volume.

GroupID: 79

DiseaseAssertion: assumed VHL

GroupSize: 58

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 58 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.499C>T) was found in 12 VHL families with 58 patients altogether.

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

GroupHPOFreeText: 36 patients had retinal angiomas with a mean age of diagnosis of 24Y, 18 patients had cHBs with a mean age of diagnosis of 30Y, 15 patients had RCCs with a mean age of diagnosis of 34Y, and 31 patients had pheos with a mean age of diagnosis of 25Y.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

PatientID: 2

KindredID: 2

Case: M, 10Y6M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: de novo mutation found: his parents were said to have tested negative for the mutation (neither parent had this R167W mutation). All other family history was negative.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: this patient was described to be practically asymptomatic, with an incidental finding: Diagnosed with adrenal incidentaloma, he had intermittent abdominal pain for 6 months (beginning at age 10Y). CT scan showed a left adrenal solid tumor (3x3cm) with no calcifications; I-MIBG was normal; he underwent an adrenalectomy for this pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: brain and spinal cord MRI, ophthal-moscopy, whole body CT scan and ultrasonography of the testes, showed no abnormalities.

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

Three patients with mutations in the VHL gene were diagnosed with pancreatic neuroendocrine tumours before the age of 18. Case 2 was a young female who developed bilateral phaeochromocytomas at 12 and underwent staged bilateral adrenalectomies at 14. At the age of 16, she was discovered to have a 2.5 cm tail of pancreas pancreatic neuroendocrine tumour. This enlarged during follow-up and additional smaller pancreatic neuroendocrine tumours in the pancreatic body became visible. A second 1 mm grade 1 pNET was also present and was completely excised. In the 7 years of follow-up since this operation, new pNETs developed within the pancreatic head, body and tail and have continued to enlarge. During a period of follow-up, she was found to have a small asymptomatic spinal haemangioblastoma. Genetic testing was done when the patient was 11-years-old and confirmed an inherited mutation in the VHL gene. She was found to have inherited a mutation in exon 3 of the VHL gene (c.499C>T, p.R167W). This missense mutation is noted in the paper as c.712C>T due to a difference in the VHL reference sequence notation used. The proband's mother died at the age of 45 from a progressive metastatic pancreatic neuroendocrine tumour diagnosed at the age of 35. The mother also had a pheochromocytoma, hemangioblastoma, and renal cell carcinoma. The proband's uncle is also described as having VHL disease and presented with pheochromocytoma, hemangioblastoma, renal cell carcinoma. The proband's maternal cousin, 'Case 3' in the paper, was a 3-year-old male who was diagnosed with VHL disease after cascade genetic screening and was found to have the same mutation as 'Case 2' in the VHL gene (c.499C>T, p.R167W). At the age of 11, he underwent resection of an abdominal paraganglioma, followed by staged bilateral adrenalectomies for phaeochromocytomas at the age of 14. Post-operative surveillance imaging detected a 1 cm body of pancreas pancreatic neuroendocrine tumour at the age of 12. Case 3's brother was a 26 year old male with a pheochromocytoma and hemangioblastoma.

PatientID:18

KindredID: D

Case: M, 46Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711, HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001737, HP:0010797, HP:0005584, HP:0030393 (pancreatic cyst, hemangioblastoma, renal cell carcinoma, endolymphatic sac tumor)

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: 0.000007 https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 2

Case: M, 21Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient has 2 siblings (patients 10 and 12) with the same mutation and pheochromocytoma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma (40mm and 30mm)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB (NM_003000.2), SDHC (NM_003001.3), SDHD (NM_003002.2), SDHAF2 (NM_017841.2), RET (exons 10–11 and 13–16, NM_020975.4), TMEM127 (NM_017849.3), MAX (NM_002382.3).

PreviouslyPublished: N/A

SupplementalData: Table 2

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: Loss of heterozygosity could be detected in tumour DNA.

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for pancreatic neuroendocrine tumours (PNETs) either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. Eight patients presented with the c.499C>T VHL gene mutation (stated as 712 C to T in the paper which used the Latif sequence as reference) causing a change of Arg to Trp at protein position 167. From family 3407, patients 30 (50-year-old male) and 31 (33-year-old male) both presented with a single radiologic PNET. From family 2301, patient 32 (34-year-old female) presented with two pathologic PNETs with metastases, and patient 33 (20-year-old female) presented with a single pathologic PNET with metastases. Unrelated patients 34 (43-year-old female), patient 35 (20-year-old female), and patient 36 (27-year-old female), all presented with three pathologic PNETs. Unrelated patient 37 (46-year-old female) presented with a single pathologic PNET. ACMG evidence codes: 'PP1' since we have co-segregation with the disease in multiple affected family members (family 3407, 5069, and 2301), 'PP4' since the patients' present phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 36

KindredID: 6015

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with three pathologic pancreatic endocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. One family with 2 patients (Family ID7) was found with a germline missense mutation in the VHL gene (R167W; c.499C>T). Patient 1 was diagnosed at 4Y and had 3 retinal hemangioblastomas at 8Y and 16Y. Patient 1 was 40 by the end of the study. Patient 2 was diagnosed at age 13Y and had no manifestations by the end of the study when they were 36Y.

PatientID: I

KindredID: 7

Case: Sex Unknown, 40Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: One other family member presented with this variant and was asymptomatic.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 4Y. presented with 3 retinal hemangioblastomas (8Y, 16Y). Age at the end of study: 40Y.

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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 41

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.R167W (c.499C>T)

LegacyVariant: N/A

GroupProblemVariantFreeText: 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: None

KindredID: 13

Case: age, sex, ethnicity unknown

DiseaseAssertion: Unknown

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Described as a positive control but not stated anything further

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely previously published - not clear where the controls came from/ how they were used.

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

PatientID: None

KindredID: 1

Case: F, 64Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0000504; HP:0006770; HP:0002666; HP:0001737; HP:0009711; HP:0002403; HP:0020036; HP:0000969; HP:0025163 (Hemangioblastoma, Abnormality of vision, Clear cell renal cell carcinoma, Pheochromocytoma, Pancreatic cysts, Retinal capillary hemangioma, Positive Romberg sign, Upper limb dysmetria, Edema, Abnormality of optic chiasm morphology)

CaseHPOFreeText: Presented at age 64 with a known large suprasellar hemangioblastoma, and history of right eye enucleation presented with worsening vision of her remaining left eye. The patient had a past history of severe VHL disease with bilateral clear cell renal cell carcinomas, bilateral pheochromocytomas, pancreatic cysts, retinal HBs, and multiple CNS HBs. Neurological exam was significant for Romberg sign and mild dysmetria of bilateral upper extremities. A visual field test of the left eye revealed new onset inferior temporal quadrantanopsia. Magnetic resonance imaging confirmed a slowly growing suprasellar hemangioblastoma within the circle of Willis with increased optic tract edema and compression of the optic chiasm.

CaseNotHPOs: HP:0007686; HP:0000496 (Abnormal pupillary function, Abnormality of eye movement)

CaseNotHPOFreeText: Left eye extraocular movements and pupillary reaction intact.

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: VHL-HBs demonstrated strong expression patterns for all receptor subtypes except SSTR3 (more info available in “Results”).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: I/1

KindredID: 2

Case: M, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Case II/3 (the patient’s son) had retina angioma with renal carcinoma. Case II/2 (his other son) also had the mutation and presented with renal carcinoma, central nervous system haemangioblastoma, pheochromacytoma and pancreatic cysts. Case III/3 (his grandson; son of Case II/2) also had the mutation and was symptomatic but specific phenotypes were not specified. Pedigree: see Figure 2.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: R167W (8702C->T)

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III/3

KindredID: 2

Case: F, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Case II/3 (patient III/3's father) had retina angioma with renal carcinoma. Case II/2 (her uncle) also had the mutation and presented with renal carcinoma, central nervous system haemangioblastoma, pheochromacytoma and pancreatic cysts. Case I/1 (her grandfather) also had the mutation and presented with haemangioblastom. Pedigree: see Figure 2.

CasePresentingHPOs: N/A

CaseHPOFreeText: This patient has developed VHL disease as mentioned in the paper, however, specific clinical presentations of the disease are not outlined.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: R167W (8702C->T)

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II/3

KindredID: 2

Case: M, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: A patient was found to have a mutation in the VHL gene (R167W (c.499C>T)). The patient inherited this mutated gene from his father (I/1) who had haemangioblastoma. His brother (II/2) also manifested renal carcinoma, central nervous system haemangioblastoma, pheochromocytoma and pancreatic cysts. One of his two children (III/3) also developed the disease. Pedigree: see Figure 2.

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant:R167W (8702C>T)

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 152

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

PatientID: 6

KindredID: 6

Case: Sex Unknown, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

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

CaseHPOFreeText: CNS and retinal capillary hemangioblastoma, pheochromocytoma.

CaseNotHPOs: HP:0006770; HP:0000107; HP:0001732 (Clear cell renal cell carcinoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

A 40-year-old woman was found with clear cell renal cell carcinoma, pancreatic endocrine tumours, and pancreatic-islet cell hyperplasia. Genetic analysis using peripheral blood revealed a germline mutation c.499C>T (p.Arg167Trp) in the VHL gene. The patient had negative family history for VHL disease. 46 months later the patient had no evidence of recurrence.

PatientID: None

KindredID: 1

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0006770, HP:0030405, HP:0004510 (clear cell renal cell carcinoma, pancreatic endocrine tumour, Pancreatic islet-cell hyperplasia)

CaseHPOFreeText: At age 40 the patient presented with left sided clear cell renal cell carcinoma, islet cell hyperplasia, and pancreatic endocrine tumour. 46 months later the patient has no evidence of recurrence.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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: Both the hyperplastic islet cells and pancreatic microadenomas stained negatively for marker upon immunohistochemical testing for hypoxia-inducible factor (HIF)-1α.

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II-5

KindredID: 1

Case: M, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This male (II-5) appears to have inherited this disease from his father, and passed it onto his son. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had pheochromocytoma described as “probable”. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition