27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summariezed the phenotypes of the families together. Family 8 was found with p.Ser80Ile mutation in the VHL gene: 1/3 members had CNS hemangioblastoma, 1/3 had RCC, 1/3 had a pancreatic lesion, and 2/3 had pheochromocytoma. ACMG PP4

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 16 was found with frameshift mutation in the VHL gene: 3/5 members had CNS hemangioblastoma, 2/5 had retinal angioma, 2/5 had RCC, and 4/5 had a pancreatic lesion.

PatientID: IV-13

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4, including this patient, are asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: None

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

LegacyVariant: p.N78S (c.446A>G)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 41 non-related patients with retinal angiomatosis between 1988 and 1999 were evaluated.

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.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: M, 62Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0009713; HP:0009711; HP:0006770; HP:0030405 (Pheochromocytoma, CNS hemangioblastoma, spinal hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, pancreatic endocrine tumour)

CaseHPOFreeText: The patient presented with clear cell renal carcinoma, and a pancreatic neuroendocrine tumor at age 62. The patient also presented with bilateral pheochromocytomas, multiple CNS and spinal hemangioblatomas, and retinal hemangioblastomas at an unknown age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.*214Cext*14(c.642A>T)

LegacyVariant: N/A

ClinVarID: 625270, http://www.ncbi.nlm.nih.gov/clinvar/variation/625270

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_loss

CivicName: *214Cext*14(c.642A>T)

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.S65L (c.194C>T) germline variant of the VHL gene was detected in an individual (ID 3404, Family 209). This patient presented with renal cell carcinoma. No family information is provided. This patient was previously published in PMID 9829912.

GroupID: 503

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with germline variants c.256C>T of the VHL gene. Member 10602 presented with moderate renal disease (RCC) and member 10603 presented with mild renal disease. 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]). 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: N/A

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: 5730

KindredID: 269

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: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals 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 published individuals could alternatively correspond to family 1005.

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

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

GroupID: 17

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family presented with the c.485G>A germline variant of the VHL gene. Member 753 presented with moderate renal disease (RCC), member 11338 had unknown renal involvement, member 696 presented with severe renal disease (RCC) and members 2368 and 699 presented with mild renal disease. 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:0009726; HP:0005584 (Renal neoplasm, 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]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

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.C162Y (c.485G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223225, https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

GroupID: 77

DiseaseAssertion: VHL

GroupSize: 13

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 13 members of this family were found to harbor the c.286C>T germline variant of the VHL gene. Members 5314, 6288, 6290, 5228 and 2499 had unknown renal involvement. Patients 5226, 6293 and 5340 presented with severe renal disease (RCC). Member 666 and 5223 presented with moderate renal disease (RCC). Members 5808 and 6380 had no renal involvement. Member 6277 presented with mild 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:0009726; HP:0005584 (Renal neoplasm, 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]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 3 individuals with this mutation are reported but relation between patients and to this patient is unknown.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

PatientID: 70

KindredID: 24

Case: F, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient no. 69) had the same germline mutation as his mother (patient no. 70). The proband himself presented with renal cell carcinoma at age 34, multiple pancreatic cysts/tumors at age 38, and pheochromocytoma at age 39.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 34.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: 237

KindredID: 89

Case: F, 46Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband presented with renal cell carcinoma at age 46.

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

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: c.642+70C>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 900551, https://www.ncbi.nlm.nih.gov/clinvar/variation/900551/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: 3'UTR alteration (c.*70C>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

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This missense mutation was confirmed in 2 families (#18 and #19). Family #18: Male proband was diagnosed with CNS hemangioblastoma at 31Y, renal cell carcinoma at 32Y, and pancreatic cysts or pancreatic tumours at 32Y (mutation confirmed); daughter diagnosed with retinal angioma at 11Y (mutation confirmed); father diagnosed with renal cell carcinoma at 52Y (passed away before diagnosis/ genetic confirmation). Family #19: female proband diagosed with retinal angioma at 12Y, renal cell carcinoma at 33Y (mutation confirmed), and multiple pancreatic cysts or pancreatic tumours at 33Y; her daughter has no clinical manifestations and her age is unknown (mutation confirmed). This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This nonsense mutation was found in two families (#30 and #31). Family #30: a male proband (patient 93) was diagnosed with CNS hemangioblastoma at 31Y (mutation confirmed). No other family information was provided. Family #31: a male proband (patient 94) was diagnosed with CNS hemangioblastoma at 56Y, renal cell carcinoma at 53Y, multiple pancreatic cysts or tumours at 53Y (mutation confirmed); his son (patient 95) was diagnosed with retinal angioma at 29Y, renal cell carcinoma at 29Y, multiple pancreatic cysts or tumours at 29Y, and pheochromocytoma at 29Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

GroupID/ KindredID: 1255NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 1255NCI. 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: 7728151; 9829911

SupplementalData: N/A

Variant: p.W88R (c.262T>A)

LegacyVariant: p.W88R (c.475T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (V62fs (c.180delG)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3563NCI. It was reported in the paper as c.393delG due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL family without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (L178Q (c.533T>A)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 29CE. It was reported in the paper as c.746T>A due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupID/ KindredID: 51CA

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 51CA. 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.E94* (c.280G>T)

LegacyVariant: E94* (c.493G>T)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 4389NCI, 1YO, 34CA

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 National Cancer Institute database, the Department of Uroglogy, Yokohama database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 4389NCI, 1YO, 34CA. 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.N78H (c.232A>C)

LegacyVariant: p.N78H (c.445A>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 625225 https://www.ncbi.nlm.nih.gov/clinvar/variation/625225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78H (c.232A>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3315NCI, 127CA

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 National Cancer Institute database and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family IDs 3315NCI and 127CA. 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: 7728151; 9829911

SupplementalData: N/A

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

LegacyVariant: p.S111N (c.545G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: frameshift_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (P86S (c.256C>T)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to two family IDs: 25BMS and 24BMS. It was reported in the paper as c.469C>T due to a difference in transcript reference. Table 5 lists all ID and mutations associated with individuals without detailed clinical information. Other phenotypes are possible, however not detailed here.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (P86L (c.257C>T)) was taken from the Department of Uroglogy, Yokohama database and the National Cancer Institute database, with an unknown number of members belonging to Family IDs 39YO, 3568NCI, 2612NCI. It was reported in the paper as c.470C>T due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMID: 7728151.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (Q96P (c.287A>C)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 98CA. It was reported in the paper as c.500A>C due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 3786NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 3786NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L178P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (C162Y (c.485G>A)) was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 11YO. It was reported in the paper as c.698G>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (L89P (c.266T>C)) was taken from multiple databases including: the Cambridge, Department of Pathology database and the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family IDs 8CE, 59CA, 21CE. It was reported in the paper as c.479T>C due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

PatientID: HGB-25

KindredID: 6

Case: Sex Unknown, 61Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29941223

SupplementalData: N/A

Variant: p.E55Rfs*12 (c.163delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/?new_evidence=false

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:minus_1_frameshift_variant

CivicName:CivicName:P25L(c.74C>T)andD126Rfs*6(c.375_376insA)andE55Rfs(c.163delG)

MultipleGeneVariants: Somatic, VHL, c.375insA (Asn131Ter) Germline, VHL, c.74C>T (p.Pro25Leu)

The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic. 8 patients had germline VHL mutations. Both peripheral blood and tumor tissue samples were sequenced using Big Dye Terminator Ready Reaction mix v.1.1 (Life Technologies, Foster City, CA). Sequencing reactions were loaded on an ABI 3100 capillary sequencer (Life Technologies) and analyzed using the Sequencing Analysis software v.3.7 (PE Applied Biosystems, Grand Island, NY). One Italian patient (HGB-27) with a germline missense mutation (c.257C>T; p.Pro86Leu) in the VHL gene was diagnosed at age 32 with multiple brainstem hemangioblastomas. The patient has a negative family history for VHL disease.

The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic. 8 patients had germline VHL mutations. Both peripheral blood and tumor tissue samples were sequenced using Big Dye Terminator Ready Reaction mix v.1.1 (Life Technologies, Foster City, CA). Sequencing reactions were loaded on an ABI 3100 capillary sequencer (Life Technologies) and analyzed using the Sequencing Analysis software v.3.7 (PE Applied Biosystems, Grand Island, NY). A 61 year old Italian male patient (Case ID HGB-25) was found to harbor a germline missense mutation (c.74C>T; p.Pro25Leu) in the VHL gene. The patient was also found to have two somatic mutations, a c.375insA was found in tumor sample 2 and a c.163delG was found in sample 1a. He was diagnosed at age 53 with cerebellar hemangioblastoma. The patient has positive family history for VHL disease.

PatientID: N/A

KindredID: 1

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: None - Neither the symptoms nor a family history of VHL disease were found in the patient.

CasePresentingHPOs: HP:0002668; HP:0002666 (bilateral metachronous pheochromocytoma; paraganglioma)

CaseHPOFreeText: The first tumor occurred at age 13 and the second at age 34 (inferred from Table 1 as this was the only case with a bilateral metachronous).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID: 34

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: F, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her daughter and son both had the same VHL gene mutation.

CasePresentingHPOs: HP:0008261, HP:0005584, HP:0006737, HP:0100561 (Pancreatic islet cell adenoma, renal cell carcinoma, Extraadrenal pheochromocytoma, spinal cord lesion )

CaseHPOFreeText: The patient was screened for disease manifestations. Abdominal magnetic resonance imaging (MRI) and computerized tomography (CT) showed pancreatic and renal masses and a para-aortic mass. At laparotomy a benign islet cell tumor, an encapsulated renal cell carcinoma of low nuclear grade and an extra-adrenal pheochromocytoma were removed. At 27 months postoperatively the patient presented with back pain and clinical signs of spinal cord compression at the T9 level. No other primary tumors could be detected despite extensive radiological investigation. Intravertebral biopsy demonstrated metastatic renal cell cancer. The spinal lesion did not respond to radiotherapy. The patient died 31 months after diagnosis and postmortem examination was declined.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: F, 53Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Free from any associated neoplasia at the time of the study and no other medical disorders.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table S1 (FormentiF VHLHIF2 SuppData1.pdf)

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223186, https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

PatientID: None (Sister 2)

KindredID: F5

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+694_340+711dup

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 816686, https://www.ncbi.nlm.nih.gov/clinvar/variation/816686/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; splice_site_variant

CivicName: c.340+694_340+711dup

MultipleGeneVariants: N/A

PatientID: I.2

KindredID: F8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

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

CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+648T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827583, https://www.ncbi.nlm.nih.gov/clinvar/variation/827583/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transition; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+617C>G

PatientID: II.6

KindredID: F8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Presented with retinal capillary hemangioma. Tumor detected at age 16.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+648T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827583, https://www.ncbi.nlm.nih.gov/clinvar/variation/827583/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transition; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+617C>G

PatientID: II.1

KindredID: 3

Case: M, 0Y4M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: The patient had an affected brother (II.2) with the same mutation and polycythemia. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 816685 https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

CAID: N/A

gnomAD: 0.00003186 https://gnomad.broadinstitute.org/variant/3-10184641-T-C

VariantEvidence: N/A

MutationType: intron_variant

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.598C>T (p.Arg200Trp)

PatientID: I.2

KindredID: F8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

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

CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+617C>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827582, https://www.ncbi.nlm.nih.gov/clinvar/variation/827582/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+648T>C

The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. Whole blood was isolated from patients and sequenced using sanger sequencing and whole-genome sequencing performed at the clinically accredited Molecular Diagnostics Laboratory at the John Radcliffe Hospital using the Hi-Sequation 4000 platform (Illumina Inc., San Diego, CA) in high-throughput mode. As well, paired-end sequencing was carried out in a single lane on the HiSeq 2500 system (Illumina).In this study, the authors show that the mutations in E1' induced dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. Three patients were found with both the c.598C>T germline VHL mutation and the c.340+770T>C mutation resulting in p.Ser179Pro mutation on potential X1 protein encoded by E1' exon. In family 2, II.1 was the only person who had both of these mutations. In family 3, brothers II.1 and II.2 had these two mutations. Biological material from the parents of these three children were not available but chuvash core haplotype analysis demonstrated that all patients were compound heterozygous with one mutation being inherited from each parent. All three cases described above had erythrocytosis.

PatientID: II.1

KindredID: 2

Case: M, 21Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: Positive family history. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 816685 https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

CAID: N/A

gnomAD: 0.00003186 https://gnomad.broadinstitute.org/variant/3-10184641-T-C

VariantEvidence: N/A

MutationType: intron_variant

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.598C>T (p.Arg200Trp)

PatientID: II.2

KindredID: 3

Case: M, 0Y6M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: The patient had an affected brother (II.1) with the same mutation and polycythemia. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232 https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

CAID: N/A

gnomAD: 0.0002016 https://gnomad.broadinstitute.org/variant/3-10191605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.340+770T>C

The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, the authors show that the mutations in E1' induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. Patient II.1 of family F4, was found to have two germline mutations in the VHL gene: R200W (c.598C>T) and c.340+694_340+711dup. This patient was diagnosed with erythrocytosis, deep vein thrombosis, intracerebral hemorrhage at age 7 (DOB: 1990). This patient's asymptomatic mother was also genetically tested and found to have the germline c.340+694_340+711dup variant of the VHL gene. Her father was not tested but is assumed to carry the R200W (c.598C>T) germline variant in VHL.

GroupID: 4

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. 

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10183764A>G

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

VHL germline mutation carriers who had an ophthalmologic examination at the Erasmus Medical Centre or the Rotterdam Eye Hospital between 1984 and 2017, and were diagnosed with retinal hemangioblastoma (RH) were included in this study. A diagnosis of RH was based on the clinical appearance of a vasoproliferative retinal tumour. Peripheral blood samples from every member that had clinically suspected VHL disease of each family were collected for VHL mutation analysis. A total of 21 patients from 10 families were included on the basis of both a VHL germline mutation and ocular manifestations. Copy number analyses were carried out by multiplex ligation dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH). Mutations were described as one of the following two groups: truncating (complete deletion, partial deletion, nonsense mutation, splice site mutation, duplication and insertion) or missense. Ocular manifestations were not reported on an individual level, but rather were broken down based on the two groups. From Pedigree (family) 14, two individuals were suspected of VHL disease and mutational analysis revealed a R64P(c.191G>C) missense variant. Both individuals from this family did not develop RH.

150 index patients with pheochromocytoma/paraganglioma were evaluated. Phenotypic data were collected and germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested. Out of 30 patients with familial presentation, 13 were clinically diagnosed as VHL syndrome. A 42 year old Asian Indian male presented with unilateral pheochromocytoma. Using PCR and Sanger sequencing through peripheral blood, genetic testing confirmed a non-familial missense mutation at c.487C>T of the VHL gene. Family history is unknown.

PatientID: 18

KindredID: 18

Case: M, 34Y0M, Asian Indian

DiseaseAssertion: pheochromocytoma

FamilyInfo:  None - Apparently sporadic

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 21

KindredID: 21

Case: F, 35Y0M, Asian Indian

DiseaseAssertion: pheochromocytoma

FamilyInfo: None - apparently sporadic

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: unilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183W (c.548C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 219158 https://www.ncbi.nlm.nih.gov/clinvar/variation/219158/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S183W (c.548C>G)

MultipleGeneVariants: N/A

150 index patients with pheochromocytoma/paraganglioma were evaluated. Phenotypic data were collected and germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested. Out of 30 patients with familial presentation, 13 were clinically diagnosed as VHL syndrome. A 20 year old Asian Indian female presented with bilateral pheochromocytoma with pancreatic cysts. Using PCR and Sanger sequencing through peripheral blood, genetic testing confirmed a mutation at c.588_588dupA of the VHL gene. Family history is positive.

The authors described the growth kinetics of 96 renal tumours in 64 VHL patients (32 males, 32 females). All patients had VHL disease with renal involvement. 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 patients, at least one or more RCC was diagnosed. However, at the time of diagnosis, an indication for treatment was not yet present. For all patients, several CT/MRI scans existed for retrospective description of tumour growth kinetics. 10-ml EDTA anticoagulated blood samples were available from each patient for mutation screening of all exons of the VHL gene. Genomic DNA from blood samples was extracted using standard methods. Small deletions/insertions or point mutations were identified by DNA sequencing followed by complete mutation screening using PCR/single-strand conformation polymorphism and denaturing high-performance liquid chromatography. A germline missense variant p.L89P(c.266T>C) was identified in two patients: patient #9 and patient #62. This mutation was noted as c.479T>C in the paper due to a difference in reference transcript used (see Table S1). No family information is available for either patient, and there is no indication these patients are related.

The authors described the growth kinetics of 96 renal tumours in 64 VHL patients (32 males, 32 females). All patients had VHL disease with renal involvement. 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 patients, at least one or more RCC was diagnosed. However, at the time of diagnosis, an indication for treatment was not yet present. For all patients, several CT/MRI scans existed for retrospective description of tumour growth kinetics. 10-ml EDTA anticoagulated blood samples were available from each patient for mutation screening of all exons of the VHL gene. Genomic DNA from blood samples was extracted using standard methods. Small deletions/insertions or point mutations were identified by DNA sequencing followed by complete mutation screening using PCR/single-strand conformation polymorphism and denaturing high-performance liquid chromatography. A germline nonsense variant p.S65*(c.194C>A) was identified in patient #5. This mutation was noted as c.407C>A in the paper due to a difference in reference transcript used (see Table S2).

PatientID: 55

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 describes 9 patients with splice mutations, including this patient.

Variant: c.464-1G>C

LegacyVariant: c.677-1G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 223220, https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0030405; HP:0009711; HP:0100634; HP:0030421 (clear cell renal cell carcinoma, pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.D92V (c.275A>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 184664 https://www.ncbi.nlm.nih.gov/clinvar/variation/184664/

CAID: N/A

gnomAD: 0.000004482 https://gnomad.broadinstitute.org/variant/3-10183806-A-T

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: D92V (c.275A>T)

MultipleGeneVariants: N/A

PatientID: 16

KindredID: 16

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030421 (Neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

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

LegacyVariant: p.P157L (c.470C>T)

CaseProblemVariantFreeText: converted from legacy notation c.470C>T; Pro157Leu; authors contacted and confirmed this error. [from reported previously Aronoff et al, 2018].

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 58

KindredID: 58

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (asymptomatic)

FamilyInfo: N/A

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0009711; HP:0100634; HP:0030405; HP:0030421; HP:0006770 (hemangioblastoma; retinal capillary hemangioma, Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm; clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

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

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: 64

KindredID: 64

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0030405; HP:0009711; HP:0030421; HP:0006770 (hemangioblastoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma; Epididymal neoplasm, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 7 - see here for more info)

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

Variant: p.R107G (c.319C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: 39

KindredID: 39

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: patient had pheochromocytoma/paraganglioma (recorded here as a neuroendocrine neoplasm)

CaseNotHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: II-a

KindredID: 1

Case: F, 16Y0M, Greek

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s 50-year-old father has VHL consisting of retinal HBs diagnosed at the age of 20 years. He also has spinal cord HBs located in the neck. He was also found to carry the mutation NM_000551.3:c.433C>T that the patient carried. The patient’s 18-year-old brother and her 20-year-old sister are phenotypically healthy and repeated biochemical evaluation and imaging studies are negative. Her paternal uncle, aunt and cousins are also phenotypically healthy with no indications from either biochemical or imaging studies as they denied further evaluation. In addition, her paternal grandfather of unknown genotype died at the age of 85 years while her paternal grandmother is alive and has no problems, being 86 years old at time of writing.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0001737 (Spinal hemangioblastoma, cerebellar hemangioblastoma, retinal hemangioblastoma, pancreatic cyst)

CaseHPOFreeText: The 16Y female patient first presented with back pain, headaches, numbness, dizziness, weakness and pain in the arms and the legs at 12Y. A hemangioblastoma in the thoracic spine and a hemangioblastoma in the neck were found. A year later, at the age of 13, multiple HBs in the right and smaller lesions in the left eye were found. Two asymptomatic cysts (2 cm and 0.8 cm) in the body of the pancreas were also found. During her recent evaluation, at the age of 16 years, MRI imaging revealed a large HB extending from the cerebellum to the Th8 vertebrae, with extensive solid and cystic nodules inside the mass and increased dimensions of the spinal cord.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145*(c.433C>T)

LegacyVariant: N/A

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

gnomAD: N/A

VariantEvidence: It has been documented that dynamic organisation of pVHL–HIF1α recognition is focally centred on Gln145 within the L7 loop, and its tumourigenic mutant Q145H abolishes almost all of the correlated dynamic motions. In this report, Q145 is substituted by a stop codon, p.Q145X. This is a nonsense mutation resulting to a truncated VHL protein that lacks the last 68 amino acids and thus its function is abolished.

MutationType: stop_gained

CivicName: Q145*(c.433C>T)

MultipleGeneVariants: N/A

This report studied the prevalence of germline variants in Japanese PPGL patients. Of the 370 PPGL original Japanese probands, this cohort consisted of 15 patients with pheochromocytoma and/or paragangliomas with germline VHL varaints. Blood samples were used to examine 7 genes: MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET, using Sanger sequencing. Of these 15 VHL patients: 10 had bilateral PCC, 4 had PCC with abdominal/thoracic PGL, and one had metastatic PPGL. The variant V84L (c.250G>C) was one of the 15 found in a patient with PPGL. Their family history or further manifestations were not detailed.

PatientID: 14

KindredID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 1

Case: M, 20Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 1, patients 1 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

CasePresentingHPOs: HP:0006748, HP:0002666; HP:0030405; HP:0010797 (adrenal pheochromocytoma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient developed PPGL at 4Y of age, and a PNET at 20Y: the 4-year-old boy with VHL disease with a history of sudoresis, headache, and abdominal pain. During evaluation, he was diagnosed with hypertension. An abdominal CT scan revealed a 5-cm heterogenous mass in the right adrenal and normal left adrenal glands. This patient underwent a right nodulectomy to preserve normal adrenal tissue. Anatomopathological diagnosis confirmed PHEO. 3 years later was a bilateral recurrence (4-cm right and 1.5-cm left nodules). The patient underwent a right-side adrenalectomy and a left-side nodulectomy. He remained without hormone replacement. After 13 years from the second surgery, the boy presented with a left-side recurrence (1.3-cm nodule) and elevated plasmatic normetanephrine levels; he underwent left-side adrenalectomy.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114S (c.340G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G114S (c.340G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, 38Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 1, patients 2 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

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

CaseHPOFreeText: The patient developed PPGL at 38Y of age, and a PNET at 38Y.

CaseNotHPOs: HP:0010797; HP:0005584; HP:0009711; HP:0001737; HP:0000107 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pancreatic cyst, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114S (c.340G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G114S (c.340G>A)

MultipleGeneVariants: N/A

GroupID: 5

Case: M, Age unknown, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88R (c.262T>A)

LegacyVariant: p.W88R (c.475T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

GroupID: 9

Case: M, Age unknown, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: Unknown

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R176Gfs*26 (c.526del)

LegacyVariant: p.R176Gfs*26 (c.739delA)

CaseProblemVariantFreeText: N/A

ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: Minus_1_frameshift_variant

CivicName: R176Gfs (c.526del)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This mutation (c.454T>C) was detected in a VHL patient with CNS hemangioblastomas, renal, epididymal and pancreatic cysts (family no. 12). The patient has no family history of VHL disease. They were identified as sporadic with their parents being excluded from having a germline mutation.

GroupID/ KindredID: 18

DiseaseAssertion: VHL

GroupSize: 14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 14 registrants belonging to the same family (18) have the germline VHL mutation.

GroupPresentingHPOs:HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0000107; HP:0002666; HP:0030393; HP:0001407 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst, pheochromocytoma, endolymphatic sac tumor, hepatic cysts)

GroupHPOFreeText: 6 had retinal hemangioblastoma, 9 had CNS hemangioblastoma, 7 had renal cell carcinoma, 8 had renal cysts, 4 had pheochromocytoma, 5 had pancreatic cysts, 2 had endolymphatic sac tumors, 1 with adnexal papillary tumor of probably mesonephric origin, and 5 had hepatic cysts.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This mutation (c.452T>C) was detected in a VHL patient with CNS hemangioblastomas and renal cell carcinoma (family no. 11). This was published in a future publication: PMID: 32179488.

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 20 has one affected member. Genetic analysis reveals mutation R161*(c.481C>T) in the VHL gene. The patient has a family history of VHL disease and presented with retinal capillary hemangioma, renal cyst and pancreatic cysts. ACMG: 'PP4' because the patient's phenotype and family history are highly specific for a disease with single genetic etiology.

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 3 has one affected member. Genetic analysis reveals mutation S65W(c.194C>G)in the VHL gene. The patient presented with renal cell carcinoma, CNS hemangioblastoma, retinal capillary hemangioma, renal cyst and pancreatic cysts. ACMG: 'PP4' because the patient's phenotypes are highly specific for a disease with single genetic etiology.

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.L158V (c.472C>G) variant (noted as p.L229V (c.685C>G) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred 91. Pheochromocytoma was not observed in any members of this kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper.

KindredID: 21

GroupID: 55

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.21 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: No phenotypic information is listed for this kindred.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

LegacyVariant: c.796C>T (p.Q266*)

CaseProblemVariantFreeText: N/A

ClinVarID: 428794, https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q195* (c.583C>T)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in 4 VHL families (Family ID 3786, 2214, 4419, 4403), using PCR and SSCP sequencing. The mutation of c.533T>C was referred to in the paper by c.746T>C due to a difference in transcript sequence. Family 3786, with VHL type 2, had 2 members with this mutation, both with hemangioblastomas of the retina and CNS, and one with pheochromocytoma. This mutation was also found in 8 individuals with VHL type 1 phenotype (family IDs 3314, 4419, 4403). In total, three of 8 individuals were identified with retinal hemangioblastomas, 5 with CNS hemangioblastomas, and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

GroupID: 3786

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

GroupHPOFreeText: both (2/2) members had retinal angioma (hemangioma) and had CNS hemangioblastoma, and 1 had pheochromocytoma

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L249P (c.746T>C)

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 4 VHL type 1 family members (family ID 3315), using PCR and SSCP sequencing. The mutation of c.332G>A was referred to in the paper by c.545G>A due to a difference in transcript sequence. 1 of 4 individuals were identified with retinal hemangioblastomas, 2 with CNS hemangioblastomas, and 2 with renal cell carcinoma. This was possibly previously published in PMID 9829911

GroupID: 4480

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

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

GroupHPOFreeText: both (2) members had CNS hemangioblastoma, and 1 member had retinal angioma (hemangioma)

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166D (c.497T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L237D (c.710T>A)

ClinVarID: 625254 https://www.ncbi.nlm.nih.gov/clinvar/variation/625254/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166D (c.497T>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: None

KindredID: 1

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: The patient had isolated left-sided hearing loss for more than 3 months. MRI showed a highly enhancing mass in the left temporal bone in the region of the jugular foramen, that measured 3.4 × 2.3 × 3.3 cm and exhibited a salt and pepper pattern in some areas. Definite histology confirmed ELST, and because a radical resection could not be guaranteed due to the highly infiltrative growth of the tumor, postoperative stereotactic radiation was initiated. The patient also had angiomatous lesions of the nasal and pharyngeal mucosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: The patient was screened for other VHL-associated tumors by fundoscopy and whole body positron-emission tomography-computed tomography, which did not show any pathological findings.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.266T>C) was recorded in the paper as c.479T>C due to a difference in transcript sequence. It was found in 6 patients with a hemangioblastomas of the central nervous system, 2 of which were stated to be primary asymptomatic. Any family information or relations is unknown. No other phenotypes described.

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.452T>C) was recorded in the paper as c.665T>C due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any family information or relations is unknown. No other phenotypes described. This (member) was published in a future publication: PMID: 32179488.

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.533T>C) was recorded in the paper as c.746T>C due to a difference in transcript sequence. It was found in one patient with a hemangioblastoma of the central nervous system. Any family information is unknown. No other phenotypes described.

KindredID: E

GroupSize: 15

DiseaseAssertion: VHL

GroupNumberMales: 6

GroupNumberFemales: 9

GroupEthnicity: N/A

GroupAgeRange: 27-55

GroupInfo: In family E, 12 patients were diagnosed with VHL disease, and 3 patients passed away before this family was screened. The missense mutation p.V170D was found in this family. It is not specified in this paper which family members were genotyped and found to have this mutation.

GroupPresentingHPOs: HP:0006880; HP:0000543, HP:0002666; HP:0001737; HP:0011732; HP:0000238; HP:0000648; HP:0005584; HP:0010797; HP:0003002; HP:0009711; HP:0002350; HP:0001407 (Cerebellar hemangioblastoma, Optic disc pallor, Pheochromocytoma, Pancreatic cysts, Abnormality of adrenal morphology, Hydrocephalus, Optic atrophy, Renal cell carcinoma, Hemangioblastoma, Breast carcinoma, Retinal capillary hemangioma, Cerebellar cyst, Hepatic cysts)

GroupHPOFreeText: Overall, family E suffers from VHL clinical type 2B. Phenotypic information for each family member is described in detail in the paper (pages 557-558.) Briefly, Patient I-1 died of of renal cell carcinoma at age 55Y. Patients II-2 and II-4 died of obstructive hydrocephalus caused by a cerebellar haemangioblastoma at the ages of 33 and 39 years respectively. The proband (patient II-7), presented with obstructive hydrocephalus caused by a cerebellar hemangioblastoma, a secondary optic atrophy, no retinal angiomas at age 55. He also has pancreatic and adrenal cysts. His elder brother (patient II-3) has a small angioma on one optic disc, bilateral renal carcinomas, and cysts in cerebellum, adrenals and pancreas. His elder sister (patient II-5) has pale optic discs, an intra-medullary hemangioblastoma, unilateral renal carcinoma, bilateral phaeochromocytomas and a unilateral mamma carcinoma. Patient III-4, has a small parapapillary angioma and an ora serrata angioma with a dilated feeder artery and draining vein present in one eye. He also has cerebellar haemangioblastomas, bilateral phaeochromocytomas, renal carcinomas, pancreatic cysts, liver cysts and medullary haemangioblastomas. Patient III-6 has pale optic discs and suffers from a small cerebellar haemangioblastoma. Patient III-7 had bilateral phaeochromocytomas. Patient III-8 developed a very small angiomain one eye at the age of 28 years. She also has bilateral renal carcinomas. Patient III-10 has retinal angiomas in both eyes and also suffers from bilateral renal carcinomas and medullary haemangioblastomas. Patient III-11 suffers from a uni-lateral renal carcinoma. Patient III-12 has optic atrophy secondary to obstructive hydrocephalus because of a cerebellar haemangioblastoma and a macular retinal angioma that detached from the retina but is still attached to the optic disc. At age 27 new angiomas started to develop in both retinas including a recurrent angioma in the left macula with exudation in the posterior pole .She also suffered from a haemangioblastoma of the medulla oblongata and bilateral renal carcinomas. Patient III-13 developed retinal angiomas in one eye at the age of 32 years. Family member III-14 has pale optic discs with a normal neurological examination.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A) Note: the cDNA change is not explicitly reported in this paper and was extrapolated from the reported protein coding change.

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256, https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/?new_evidence=true

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

GroupID: 51

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.L188P (c.563T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625266 https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation p.S80N (c.239G>A) was found in 2 VHL patients. Both were said to have retinal hemangioblastomas, while other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849

GroupID: 42

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A - only 1 patient reported here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Other manifestations are possibly but not clearly reported

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.337C>T (p.Arg113Ter)) was found in 2 patients stated to have retinal HBs. Other manifestations are possible but not clear. This is possibly previously published in PMID: 15300849

PatientID: None

KindredID: 6

Case: F, 53Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's sibling was the proband and had the mutation c.349T>G presenting with renal cell carcinoma, retinal angioma, hemangioblastoma, abnormality of the pancreas, and epididymal or ovarian cystadenoma.The patient's mother, aunt, grandmother, brother 1 and 2, and sister 3 all passed before they could undergo genetic testing but had a variety of VHL presentations. The patient's third nephew were confirmed to have this genetic mutation. The nephew had hemangioblastoma and retinal angioma at age 13. Additional familial phenotypes can be found in Table 1.

CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

CaseHPOFreeText: The patient presented with abnormality of the pancreas at age 53.

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

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

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

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

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117G (c.349T>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: Sex Unknown, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. Patient's son who was confirmed to have this mutation presented with hemangioblastoma at age 12. The patient's mother, aunt, grandmother, brother 1 and 2, and sister 3 all passed before they could undergo genetic testing but had a variety of VHL presentations. The patient's first sister and third nephew were confirmed to have this genetic mutation. The first sister presented with abnormality of the pancreas at age 53. The nephew had hemangioblastoma and retinal angioma at age 13. Additional familial phenotypes can be found in Table 1.

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

CaseHPOFreeText: The patient presented with hemangioblastoma at age 36. At age 40 he/she presented with pancreatic cysts or tumours. At age 44 the patient had retinal angioma, renal cell carcinoma, and epididymal or ovarian cystadenoma.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

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

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117G (c.349T>G)

MultipleGeneVariants: N/A

PatientID: 30

KindredID: 30

Case: F, 27Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

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

CaseHPOFreeText: CNS hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

Variant: p.L128P (c.383T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1208816, https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L128P (c.383T>C)

MultipleGeneVariants: N/A

PatientID: 38

KindredID: 38

Case: M, 22Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family positive for VHL. No further details provided.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

PatientID: IV:6

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient had two siblings both of whom carried the P25L mutation. One was asymptomatic (IV:4) whereas another (IV:2) presented with retinal hemangioma and renal cysts. Her cousin (IV:7) was diagnosed at the age of 47 years with renal cell carcinoma and subsequently died at the age of 48 years. Her great grandmother (I:2) had died of a brain tumor in her late 50s. Her grandfather (II:3) had a brain tumor at the age of 53 years and died aged 78 years. As well, her grandfather's sister (II,1) reportedly died of stomach cancer in her 80s. Of the 13 family members tested, V:2, IV:4, IV:6, III:2, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: III:11

KindredID: 1

Case: F, 75, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:2 and III:3). The patient's sister (III:2) had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her niece, (IV:2) had three children and one was found to carry the mutation. The patient's brother (III:3) had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation (IV:7). The patient had three unaffected children who did not carry the mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Ongoing clinical follow up of the individuals with P25L over a period of 5 years has continued to show no evidence of additional clinical involvement of VHL disease.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

A study of 34 Polish families revealed germline mutations in 30 families using DNA isolated from peripheral blood luykocytes to sequence through PCR and Quantitative Southern analysis. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation (c.194C>T) was found in a single VHL patient and 2 VHL families with multiple affected individuals. The patient had hemangioblastomas of the central nervous system (family no. 1). The VHL family of 4 affected individuals had one patient with retinal hemangioblastomas, 3 with hemangioblastomas of the central nervous system, and one with renal cell carcinoma (family no. 2). The VHL family of 12 individuals had 10 with retinal hemangioblastomas, 3 with renal cell carcinoma, and 12 with hemangioblastomas of the central nervous system (family no. 3). Supporting evidence of pathogenicity since there is cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 5 patients were found to have the above mutation (c.461C>T). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry.The other 4 patients were stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

GroupID: 22A

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 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.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID: 7B

DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 158

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 158 patients with the given mutation were grouped as group 7(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: No recorded islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

GroupPreviousTesting: N/A

PreviouslyPublished: 7987306

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

The genetic testing program for VHL disease included 17 families, ten of which had definite VHL disease and seven had possible VHL disease. 17 families (n=109 individuals) were tested for VHL mutations. Mutation analysis was performed by direct sequencing of the VHL gene. Mutations were identified in 36 patients. Mutations-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. Tumor status and phenotypes were documented at initial screening and at follow ups. 1 individual from family 21 was tested positive for p.R82P mutation. 1 hemangioblastoma was diagnosed at initial screening, 2 additional hemangioblastoma, bilateral retinal capillary hemangioma, kidney cysts, pancreatic cysts, 1 renal cell carcinoma were diagnosed at follow-ups. The patient deceased at last follow-up. ACMG evidence codes: 'PP4' because the patient's phenotypes are highly specific for a disease with single genetic etiology.

42 CNS hemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre were analyzed for VHL mutations. One patient of 17 presenting with VHL germline mutations presented with the N78S (c.233A>G) mutation (stated as c.446A>G in the paper which used the Latif sequence as reference). Single strand conformation polymorphism and southern blotting for variant identification in the DNA found in blood samples. The patient was established as having VHL disease by standard of Neumann at al., 1987. The patient presented with three cerebellum tumors, with LOH in each.

PatientID: 10

KindredID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient 10 and 4 are related with the same p.L89P mutation and cerebellar hemangioblastomas. Their exact relation was not clear.

CohortInfo: A total of 42 CNS haemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient presented with a VHL-related tumor in the cerebellum.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L89P (c.479T>C)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France). No variants were found in 96 control cases. This missense mutation, c.473T>C, was found in two VHL type 1 family members (patient no. V252). One unaffected individual family member was tested and found to not have the germline mutation. No patient information was provided and no additional family members were screened.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The L118P (c.353T>C) missense mutation was found in 3 VHL type 1 (no pheochromocytoma) family members (patient/proband no. V27). Ten unaffected family members were screened with no evidence of the L188P variant. This family was stated as being previously published in PMID 15300849.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The W117C (c.351G>T) missense mutation was found in 4 VHL type 1 (no pheochromocytoma) family members (patient/proband no. V13).

PatientID: V345

KindredID: V345

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 92 unrelated patients with VHL disease.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient was classified as VHL type 2B family meaning that she had a pheochromocytoma and presence of renal and pancreatic manifestations.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162W(c.486C>G)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:C162W(c.486C>G)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The V62Cfs*5 (c.180del) mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V9). The variant was reported as c.179del and mapped to c.180del.

Renal cell carcinomas from 31 patients (22 of which were confirmed clear cell renal cell carcinoma) were obtained from the CentreLeon Berard (Lyon, France) and were analyzed for mutations in the VHL gene. SSCP analysis of exon 2 and 3 and of a 450-nucleotide region in the last one third 3'-region of exon 1 of the VHL gene was used to detect mutations. Tumor 3087 (non metastatic) was taken via nephrectomy from a 68 year old male with clear cell renal cell carcinoma. Two mutations were detected in this tumor sample. Comparison with peripheral blood leukocytes showed that the P61P (c.183C>G) mutation in exon 1 was present in non-tumor tissue as well, demonstrating that this is a germline mutation. This silent mutation was reported as a rare polymorphism in Sekido et al, 1994 (PMID: 8183553). A somatic mutation L181P (c.551T>C) in exon 3 was also detected in tumor 3087.

PatientID: III-7

KindredID: 1

Case: M, Age Unknown (deceased), Middle Eastern

DiseaseAssertion: VHL

FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

CasePresentingHPOs: HP:0010797; HP:0006770 (hemangioblastoma; clear cell renal cell carcinoma)

CaseHPOFreeText: Member had clear cell renal carcinomas that were the main cause of mortality, in addition to hemangioblastomas

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: Lacked evidence of any pheos.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Trp117Cys (c.564G>T)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A