PatientID: 1

KindredID: 95

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: one pheochromocytoma was detected in this patient

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

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: LOH detected

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 152

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002894 (neoplasm of the pancreas)

CaseHPOFreeText: Patient presented with a pancreatic tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/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: Loss of heterozygosity

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 138 (Second cousin)

KindredID: 18

Case: M, 49Y0M, 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:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseHPOFreeText: This patient presented with pheochromocytoma (11Y). Age of diagnosis of retinal angioma is unknown.

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0010797 (Renal cell carcinoma, 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

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

PatientID: 7

KindredID: 7

Case: F, 40Y0M, Korean

DiseaseAssertion: Assumed VHL

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405; HP:0006880 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic endocrine tumor, cerebellar hemangioblastoma)

CaseHPOFreeText: The patient presented with adrenal pheochromocytoma. She also had other tumours, including renal cell carcinoma, pancreatic endocrine tumor, cerebellar hemangioblastoma (see table 3).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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, 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: V-9

KindredID: 1

Case: M, Age Unknown, Iranian

DiseaseAssertion: asymptomatic

FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation, one of which was this patient. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: III-16 (proband)

KindredID: 1

Case: M, 52Y0M, Iranian

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: IV-19

KindredID: 1

Case: F, 25Y0M, Iranian

DiseaseAssertion: assumed VHL

FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: HP:0002666; HP:0006880 (Pheochromocytoma, cerebellar hemangiomblastoma)

CaseHPOFreeText: Patient had a unilateral PCC and cerebellar HB at 23Y which was surgically removed at the time. She presently has no abnormal findings.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: F, 59Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0010797, HP:0030405, HP:0000107(hemangioblastoma, pancreatic endocrine tumour, renal cyst)

CaseHPOFreeText: This patient underwent abdominal CT; multiple renal cysts, a hypervascular mass in the pancreatic body, and a cystic mass in the pancreatic head and tail were found. Pylorus preserving pancreaticoduodenectomy was performed in this patient. Two months after surgery, gait disturbance appeared. MRI of the brain revealed multiple enhancing masses in both cerebellums, which were pathologically found to be hemangioblastoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Hereditary PNET with a confirmed germline mutation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 2338

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

GroupHPOFreeText: all 4 members had retinal angioma (hemangioma), 3 had CNS hemangioblastoma, 3 had pheochromocytoma, and 1 member had RCC

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 2 2338NCI)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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-

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1 (III:1)

KindredID: 1

Case: F, 39Y0M, Persian

DiseaseAssertion: VHL

FamilyInfo: 4 sisters were treated with bilateral adrenal mass resection. Patient 2 died at 23Y and patient 3 died at 21Y due to complications associated with VHL. 2 years later, 3 of their other sisters were found to have the mutation. It is assumed that all 5 of them had the VHL mutation. Their mother and the siblings examined normal, and the father had passed earlier and had a family history of hypertension.

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

CaseHPOFreeText: Presented with cerebral hemorrhage and coma at the age of 29 years. Bilateral malignant pheochromocytoma (adrenal mass resection) and retinal angiomas. Malignant pheochromocytoma confirmed with biochemical tests and pathology with involvement of liver, pancreas, kidneys and inferior vena cava.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: 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: 192

KindredID: 73

Case: F, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 191, has a mother who was also found to have the same germline mutation. The proband's mother (patient 192) had a retinal angioma at 25, a CNS hemangioblastoma at 38, and multiple pancreatic cysts/tumors at 52.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 38, retinal angioma at 25, and multiple pancreatic cysts/tumors at 52.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as a later paper by Wang et al., 2018 (PMID: 29330336).

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 220

KindredID: 82

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister both presented with renal cell carcinoma at ages 49 and 27, respectively. Their mother also had a CNS hemangioblastoma at 45, and their sister had a retinal angioma at 30. No genotyping information was available for either family member.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at age 22, and a pheochromocytoma at age 36.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

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: 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: N/A

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

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

CaseHPOFreeText: Patient had VHL disease and their surgically removed tissue sample clear cell renal cell carcinoma tissue sample was used as positive control.

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)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: IV-50

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-50) appears to have inherited this disease from his mother. 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. The patient had pheochromocytoma and retinal angiomas, further details were not provided. He also presented with Vitamin-D-Resistant rickets, likely inherited from his mother, and non-VHL affected grandmother.

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-9

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-9) appears to have inherited this disease from her father, along with many of her 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. She 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: 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: III:8

KindredID: 1

Case: F, 45Y0M, 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:0002666 (pheochromocytoma)

CaseHPOFreeText: patent had bilateral pheo with an age of onset at 26Y, and operation was performed at 30Y

CaseNotHPOs: HP:0006880; HP:0030405; HP:0001737; HP:0000107; HP:0002668 (cerebellar hemangioblastoma, 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: 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

KindredID: 1

Case: M, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Eight patients whose pheochromocytomas were suggestive of VHL but were negative for a VHL abnormality both by PCR-Sanger sequencing and by quantitative multiplex PCR of short fluorescent fragments (QMPSF).

CasePresentingHPOs: HP:0010797, HP:0002666, HP:0030405, HP:0006748 (Hemangioblastoma, Pheochromocytoma, Pancreatic endocrine tumor, adrenal pheochromocytoma)

CaseHPOFreeText: Patient developed hemangioblastoma at age 16. At age 17 he developed right pheochromocytoma, pancreatic endocrine tumour, and a small left adrenal nodule later stated to be an adrenal pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient is believed to be the same as a patient published in 30731206. That paper offers more updated information on this patient.

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 5.7%.

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: 42

KindredID: 5069

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 41) has the same VHL mutation and presents with five pathologic pancreatic endocrine tumours.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with three pathologic pancreatic endocrine tumours.

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)

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 32

KindredID: 2301

Case: F, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 27

KindredID: 27

Case: F, 26Y0M, Asian Indian

DiseaseAssertion: Assumed VHL

FamilyInfo: Positive family history

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0030405 (pheochromocytoma; paraganglioma; pancreatic endocrine tumor)

CaseHPOFreeText: patient had bilateral pheochromocytoma and sympathetic paraganglioma; and PNETs

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

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

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

PatientID: 10

KindredID: 10

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0100634; HP:0009711 (hemangioblastoma, neuroendocrine neoplasm, retinal capillary hemangioma)

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma, a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm), and a retinal hemangioblastoma.

CaseNotHPOs: HP:0030421; HP:0006770; HP:0030405 (epididymal tumour, clear cell renal cell carcinoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: Patient was recorded without the manifestations of: an epididymal tumor, CCRCC, and a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm)

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 50

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 49

Case: F, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

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: 88

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.500G>A variant causing a Arg167Gln missense mutation (noted in the paper as c.713G>A due to Latif reference transcript being used). It was noted that this family had patients with pheochromocytoma's.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified. It was noted that this family had patients with pheochromocytoma's.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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

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

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: 16

KindredID: 11

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 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

PatientID: None

KindredID: F (proband)

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: His mother was also found to have this mutation and she had renal cell carcinoma at age 49.

CasePresentingHPOs: HP:0009711, HP:0002666, HP:0000085 (retinal capillary hemangioma, pheochromocytoma, Horseshoe kidney)

CaseHPOFreeText: Patient developed retinal hemangiomas and unilateral pheochromocytoma at the age of 27 years. Abdominal CT showed also horseshoe kidneys.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F8

Case: Sex unknown, 35Y0M, Spanish

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Multiple lesions were found with the patient’s retinal hemangioma. Age of onset is 35Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F18

Case: Sex unknown, 33Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F34

Case: Sex unknown, 33Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

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

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Proband's father (M) had an operation for spinal tumor 9 years before, and renal cell carcinoma was detected during the screening. Proband's uncle (M) had an operation for a benign cervical spinal mass 27 years before, and a chondrosarcoma of the right femur 10 years before. He also had renal cell carcinoma. Both died owing to the disease, and no genotyping information is available for either. Proband's sister (20, F) was healthy. See Figure 1 for pedigree, including extended family phenotypic information.

CasePresentingHPOs: HP:0006748, HP:0009711 (adrenal pheochromocytoma, retinal capillary hemangioma)

CaseHPOFreeText: The proband had bilateral adrenal pheochromocytoma and a hemangioblastoma in the right eye. She was diagnosed with VHL type 2B. Four years post surgery, the patient remained well with no clinical or radiological evidence of recurrent disease. At her last visit, abdominal ultrasonography showed an angiomyolipoma 8 mm in diameter in her left kidney.

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)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

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: 15

KindredID: 6

Case: F, 22Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 1 other member of this family presented with the same variant. Patient 16 (Gen 2) presented with bilateral pheochromocytoma.

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

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

CaseHPOFreeText: Sympathetic paraganglioma and bilateral pheochromocytoma. Age of onset for pheochromocytoma and paragangliomas is stated as 11Y and 22Y but it is not clear which age pertains to which phenotype.

CaseNotHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0030405 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma, Pancreatic endocrine tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 110CA

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 110CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, ithout 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.G57Rfs*75 (c.167_168insA)

LegacyVariant: (c.380insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA916084344 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.167_168insA

gnomAD: N/A

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

MutationType: plus_1_frameshift_variant

CivicName: G57fs (c.167_168insA)

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: None

KindredID:72

GroupID: 45

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.72 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is present in this kindred.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: This study investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. No other information about disease presentation within members of a kindred could be inferred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A?dataset=gnomad_r2_1

VariantEvidence:

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

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

PatientID: None

KindredID: 5143

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Two members of this family were diagnosed with VHL Type 2B. Both members presented with pheochromocytoma, renal cell carcinoma and CNS hemangioblastoma and one of these also presented with retinal angioma.

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

CaseHPOFreeText: Diagnosed with CNS hemangioblastoma, pheochromocytoma, RCC and VHL Type 2B.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.713G>A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Variant reported as 713, G to A (Arg to Gln), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.500G>A, p.Arg167Gln (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

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

GroupID/KindredID: 6105

DiseaseAssertion:VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This group is a family of six people with the same mutation.

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

GroupHPOFreeText: 4/6 family members had renal cell carcinoma. 3/6 family members had pheochromocytoma and hemangioblastoma. 2/6 family members had retinal angioma. One family member had cysts- not specified what type.

GroupNotHPOs: HP:0030405 (Pancreatic endocrine tumour)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.713G>A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Variant reported as 713, G to A (Arg to Gln), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.500G>A, p.Arg167Gln (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G>A)

MultipleGeneVariants: N/A

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

PatientID: None

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: Presented with bilateral retinal angiomas. Abdominal CT revealed a pancreatic head mass and in surgery multiple 1 to 2 mm bilobar liver lesions were revealed. These were histologically confirmed to be metastatic islet cell disease.The primary pancreatic tumor that involved the superior mesenteric artery also demonstrated an islet cell neoplasm.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405, HP:0000107, HP:0000138 (pancreatic endocrine tumour, Renal cyst, Ovarian cyst)

CaseHPOFreeText: The patient initially only presented with bilateral small ovarian cysts. On follow up four years later, it was found that she had two hypervascular pancreatic head tumours <1cm in diameter, a complex left renal cyst, and enlarged ovarian cysts. A pancreaticoduodenectomy and left heminephrectomy was performed, revealing two <1-cm islet cell tumours and a complex renal cyst with severe cellular atypia but no invasive maligancy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 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: 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

GroupID: 509

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

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

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 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: None

KindredID: 14

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.R167Q (c.500G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: VHL 9

KindredID: VHL 9

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Two samples of VHL hemangioblastomas were represented here (.1, .2)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A - although likely duplicated in 24132471

SupplementalData: Yes - See 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: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: Somatic, VHL, c.292C>A p.Tyr98*

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

PatientID: N/A (case)

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0006765 (Hemangioblastoma; Retinal capillary hemangioma; Chondrosarcoma)

CaseHPOFreeText: Patient presented at 48Y with pain in her left arm. She was diagnosed with VHL at 25Y. She had surgery for CNS HB at ages 26, 28, 39, and 45Y. She also had retinal HB and underwent a coagulation procedure at 26Y. A lytic lesion was found in the left distal ulna (clear cell chondrosarcoma)

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemnagioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: An unspecified gene panel analysis was performed, where no additional mutations were found (except for a non-pathogenic, variant of the ATM gene (c.1810C>T; p.(Pro604Ser))).

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Loss of wild type VHL during tumour development.

MutationType: missense_variant;transition