PatientID: 11

KindredID: 11

Case: 30Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: No family history

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0001737 (hemangioblastoma; retinal capillary hemangioma; renal cyst; pancreatic cysts)

CaseHPOFreeText: Aged 30Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS angiomas, retinal angiomas, renal cysts and pancreatic cysts all diagnosed at 30Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 19

Case: F, 8Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Positive. The patient's cousin was the proband (1). The proband's mother (2) and uncle (7) carried the mutation and presented with symptoms. The proband's first cousin once removed (22) was also found to have the mutation but was asymptomatic.

CohortInfo: 20 unrelated VHL families from an ethnically diverse cohort containing both affected and unaffected individuals.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666, HP:0001732, HP:0000077, HP:0010797 (retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma, abnormality of the pancreas, abnormality of the kidney, hemangioblastoma)

CaseNotHPOFreeText: The patient did not have epididymal or ovarian cysts.

CasePreviousTesting: N/A

PreviouslyPublished: 31368132

SupplementalData: Supplementary file 1.

Variant: p.W88* (c.263G>A)

LegacyVariant: p.W88* (c.476G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 19

Case: F, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's son was the proband (1) and carried the mutation but was asymptomatic. The proband's uncle (7) carried the mutation and presented with symptoms. The proband's cousin (9) and first cousin once removed (22) were also found to have the mutation but were asymptomatic.

CohortInfo: 20 unrelated VHL families from an ethnically diverse cohort containing both affected and unaffected individuals.

CasePresentingHPOs:HP:0010797, HP:0005584, HP:0001732, HP:0000077 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, abnormality of the kidney)

CaseHPOFreeText: The patient presented with a hemangioblastoma at ages 17, 24, 30. At age 25 she presented with renal cell carcinoma and abnormalities of the kidney and pancreas.

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

CaseNotHPOFreeText: The patient did not have epididymal or ovarian cysts.

CasePreviousTesting: N/A

PreviouslyPublished: 31368132

SupplementalData: Supplementary file 1.

Variant: p.W88* (c.263G>A)

LegacyVariant: p.W88* (c.476G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 43Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Positive family history but no further information

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584; HP:0030424 (hemangioblastoma, pancreatic cyst, renal cell carcinoma, epididymal cyst)

CaseHPOFreeText: Patient had an age of diagnosis of VHL at 43

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.W88* (c.264G>A) OR (c.263G>A) (see evidence statement)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 936684 https://www.ncbi.nlm.nih.gov/clinvar/variation/936684/ OR 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: stop_gained

CivicName: W88*

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: Sex Unknown, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive family history. The patient's mother had the same VHL mutation and presented with CNS hemangioblastoma.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

CasePresentingHPOs: HP:0006770, HP:0001732 (clear cell renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText: The patient presented with clear cell renal cell carcinoma at age 34 and multiple pancreatic cysts or tumours at age 38.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0010797 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24986515

SupplementalData: N/A

Variant: p.W88* (c.263G>A)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 71

KindredID: 25

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 8YO

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 8YO. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88S (c.263G>C)

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

PatientID: 5654

KindredID: 266

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: 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]). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this patient is previously reported in PMIDs ​​12202531 and/or 9829912. Unclear if the patient reported in both these other papers is the same as he current patient.

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

Variant: p.W88S (c.263G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

PatientID: II-I

KindredID: 2

Case: M, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history reported for this patient.

CasePresentingHPOs: HP:0006880; HP0005584; HP:0030405 (cerebellar hemangioblatomas, renal cell carcinoma; pancreatic endocrine tumor)

CaseHPOFreeText: Patient first presented with VHL-related clinical manifestations at age 49Y0M. He had cerebellar hemangioblatomas, bilateral RCC and nephrectomy, as well as pancreatic surgery for his PNENs. He was diagnosed with VHL type 1 and passed away at age 54Y0M (see table 2).

CaseNotHPOs: HP:0001737; HP:0000107; HP:0006748; HP:0002668(pancreatic cysts; renal cyst; adrenal pheochromocytoma; paraganglioma)

CaseNotHPOFreeText: Patient negative for pancreatic cysts, renal cysts, adrenal pheochromocytoma and paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 39Y0M, Ethnicity Unknown

DiseaseAssertion: Clear cell renal cell carcinoma

FamilyInfo: N/A

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

CaseHPOFreeText: A 57-year-old Caucasian woman with an unremarkable past medical history presented with lumbar pain. Physical examination revealed a mass on the right flank. An FDG-PET scan revealed a renal mass highly suggestive of malignancy, signs of liver spread, and pelvic and lumbar spinal cord bone metastases. Open right radical nephrectomy was performed. The histopathologic report revealed Fuhrman grade 4 advanced ccRCC. New response assessment after 2 cycles of treatment revealed disease progression with new liver and bone lesions and clinical deterioration. In August 2015, a new solitary bone metastasis arose in the skull, whereas others remained with no change.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary eTable1

Variant: p.W88L (c.263G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750675, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351750675

gnomAD: N/A

VariantEvidence: VHL and MTOR variants were not explicitly stated to be germline in the text but were not present in Supplementary eTable 1 where variants present in tumor/metastasis and absent in blood are listed. The number of tumor mutations (single nucleotide variants and indels) leading to nonsynonymous coding or loss-of-function (LOF) variants in the primary tumor was 160. Tumor mutations refer to those detected in the tumor but absent in the blood. In total, 116, 76, and 65 mutations were detected in each of the 3 tumor regions and from these, 41 were shared. Among the shared tumor mutations, 39 were missense variants and 2 were LOF variants caused by frameshifts. The variants affecting genes frequently mutated in ccRCC were detected in all tumor samples analyzed: VHL (c.263G>T; p.W88L), BAP1 (c.1359dup; p.E454Rfs*15), and MTOR (c.5920T>C; p.Y1974H). For a comprehensive list of somatic variants see Supplementary eTable1.

MutationType: missense_variant;transversion

CivicName: W88L (c.263G>T)

MultipleGeneVariants: Germline, MTOR, c.5920T>C (p.Tyr1974His) MultipleGeneVariants: Somatic, BAP1, c.1359dup (p.Glu454Argfs*15)

PatientID: None

KindredID: 8

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Renal cell carcinoma and pancreatic cyst or tumor (unspecified).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.W88S (c.263G>C)

LegacyVariant: c.476G>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

GroupID: 6B

DiseaseAssertion: assumed VHL

GroupSize: 9

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 33.8Y +/- 17.6Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 3 families with 13 members total were described. it is unclear how many distinct families are reported in group 6B. 9 individuals were described. Phenotypic information was given for this mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

GroupHPOFreeText: 7 of the 9 members presented with CNS hemangioblastoma (mean age of 29.9Y), 2/9 had retinal angiomas at 25Y and 35Y, 1 had renal cell carcinoma (at 30Y), pancreatic cysts in 2 members (with an age of onset of 30 and 31Y), and 1 member with a genital system tumor (epididymis or broad ligament) at 24Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No patients were given with pheochromocytoma

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336; 28388566

SupplementalData: N/A

Variant: p.W88S (c.263G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A GroupEthnicity: Japanese GroupAgeRange: N/A

GroupInfo: The 5 patients are grouped based on both having the same mutation. They are unrelated to one another.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: 5/5 patients in this group presented with RCC.

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

Variant: p.W88S (c.263G>C)

LegacyVariant: p.W159S (c.476G>C)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Nucleotide deletion (i.e. 476G>C) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.263G>C (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

PatientID: 60

KindredID: 23

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 23) had three family members genetically confirmed with the mutation: his son/ patient 61 (asymptomatic at time of assessment), his daughter/ patient 62 (asymptomatic at time of assessment), and his cousin/ the son of his Aunt 3/ patient 68 (CNS hemangioblastoma at 26). The proband also had 5 family members who passed away before they could be confirmed with the mutation: his father/patient 63 (CNS hemangioblastoma at 35, retinal angioma at 35); his sister/ patient 64 (CNS hemangioblastoma at 24 and multiple pancreatic cysts/tumors at 31); his aunt 1/ patient 65 had a CNS hemangioblastoma at 35; his aunt 2/ patient 66 had a CNS hemangioblastoma at 20; and his aunt 3/ patient 67 had a CNS hemangioblastoma at 44.

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

CaseHPOFreeText: The proband presented with CNS hemangioblastoma and retinal angioma at 25, renal cell carcinoma and multiple pancreatic cysts/tumors at 30.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.W88S (c.263G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2220; https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/?new_evidence=true

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

PatientID: V266

KindredID: V266

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88S (c.263G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A