PatientID: 100

KindredID: 100

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Paraganglioma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: The patient had multiple paragangliomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1. There is additional tumour specific information in Supplemental Table 2.

Variant: p.R64P (c.191G>C)

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

gnomAD: N/A

VariantEvidence: Membrane CA9 immunostaining was observed (supplemental table 1).

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A

PatientID: 40/41

KindredID: 40/41

Case: Sex Unknown, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Patient data is extracted from two rows assumed to be referring to the same patient (i.e. tumor samples 40 and 41 in Supplementary Table 1a). Carbonic anhydrase 9 (CA9) mRNA level of 795.70 (PCC) and 815.38 (PCC) were detected. Membrane CA9 immunostaining was observed in both PCC samples.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>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 using peripheral blood. 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. 6 (3 adults and 3 children) members from family 6 were tested positive with c.99_100InsA mutation. 2 adult and 1 pediatric patients were affected at initial screening. Another adult patient was affected by VHL disease at follow up. The other 2 children were asymptomatic both at initial screening and at last follow up. 13 (7 adults and 6 children) members from family 7 were tested positive with c.99_100InsA mutation. 9 members were affected by clinical VHL disease in total by the final follow up. The other 4 patients (whom were all pediatric) were asymptomatic at last follow up. ACMG evidence codes: 'PP4' because the patients' family history are highly specific for a disease with single genetic etiology.

PatientID: None (II)

KindredID: 7

Case: Sex and Ethnicity unknown; Age <18Y0M

DiseaseAssertion: Asymptomatic

FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

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.

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.

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 17 was found with p.Arg161* mutation in the VHL gene: 2/2 members had CNS hemangioblastoma, 1/2 had retinal angioma, and 1/2 had RCC. ACMG PM1

GroupID/ KindredID: 141CA

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 141CA. 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.L188Rfs*14 (c.563delT)

LegacyVariant: FS (c.776delT)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423679 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.563delT

gnomAD: N/A

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

MutationType: minus_1_frameshift_variant

CivicName: L188fs (c.563delT)

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 (c.464-2A>C) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 4BMS. It was reported in the paper as c.677-2A>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.

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 (H115Y (c.343C>T)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 59CE. It was reported in the paper as c.556C>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.

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.

PatientID: 23

KindredID: 23

Case: 23Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0030393; HP:0005584; HP:0009711 (hemangioblastoma; endolymphatic sac tumor; renal cell carcinoma; retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78I (c.233A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223169 https://www.ncbi.nlm.nih.gov/clinvar/variation/223169/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78I (c.233A>T)

MultipleGeneVariants: N/A

PatientID: 24

KindredID: 24

Case: 17Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Null (Complete deletion)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Stated in paper as “del VHL”; complete vhl gene deletion

MutationType: deletion (exon_loss_variant)

CivicName: DELETION

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: PCR and multiplex ligation-dependent probe amplification (MLPA)

SamplingMethod: assumed: peripheral blood leucocytes (from PMID: 12114495 described in paper)

PMID: 28662711

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 5

KindredID: 5

Case: M, 15Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with a peripheral tumor in his right eye at the age of 13. He exited the trial in 2016 with no changes to the tumor size after the administration of propranolol over a one year trial.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Information obtained from Table 2.

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history revealed hemangioblastomas and pheochromocytomas.

CohortInfo: Two patients with parasympathetic paraganglioma, previously published in 19336503 were studied.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: At age 7, the patient had a malignant sympathetic paraganglioma in the retroperitoneum with regional lymph node metastases. Eight years later, the patient presented with a parasympathetic paraganglioma of the left carotid body.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No other tumours were found.

CasePreviousTesting: SDHB/SDHC/SDHD

PreviouslyPublished: 19336503

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: Case 2 showed LOH for markers D3S1597 and D3S1263 and was homozygous (not informative) for marker D3S1435.

MutationType: missense_variant; transition

CivicName: Y98H (c.292T>C)

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 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

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.

PatientID: 26

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 S6 describes 3 patients with small insertions, including this patient.

Variant: p.R69Afs*63 (c.204dup)

LegacyVariant: c.417insG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant, duplication

CivicName: R69Afs*63 (c.204_205insG)

MultipleGeneVariants: N/A

PatientID: 65

KindredID: 65

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (likely family 17 - see here for more info)

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

Variant: p.V166Sfs*4 (c.496_506del11)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223229 https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: V166Sfs*4 (c.496_506del)

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

GroupID: 6

Case: 31Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.182_185delCCGT) was found in 1 VHL family with a single patient.

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

CaseHPOFreeText: patient had retinal capillary hemangioma diagnosed at 31Y and cerebellar hemangioblastoma diagnosed at 30Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.P61Rfs*5 (c.182_185delCCGT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658820712 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.182_185del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P61FS (c.182_185delCCGT)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.509T>G), affecting residue on the surface of pVHL, was found in a VHL family of 4, 3 with retinal hemangioblastomas, 1 with renal cell carcinoma diagnosed at 33Y, and 1 with pheochromocytoma diagnosed at 29Y. This mutation was reported in the paper with an incorrect cDNA written as c.509T>C, however correct translation should be c.509T>G given the Latif et al. (1993): c.722T>G (Val170Gly)

GroupID: 53

DiseaseAssertion: assumed VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 8 of the 573 patients discussed in this paper were found to have identical variants. This mutation (S65W (c.194C>G)) was found in 1 VHL family with 8 patients.

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

GroupHPOFreeText: 6 had retinal hemangioblastoma, 5 had cerebellar hemangioblastomas, and 1 had renal cell carcinoma. Mean ages for each diagnosis follows: 32 (RH), 39 (CHB), 56 (RCC - with one patient)

GroupNotHPOs: HP:0002666 (pheochromcytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65W (c.194C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: II:4

KindredID: 1

Case: F, Age Unknown (deceased), Chinese

DiseaseAssertion: VHL

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 26

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: one cerebellar hemangioblastoma was detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V170F (c.508G>T)

MultipleGeneVariants: VHL, Somatic, c.576del13 (p.Asn193Met*9)

GroupID: 1

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: Exon 1-2 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10182301_10188764del; c.-1231_463+444del6464

MutationType: exon_loss_deletion

CivicName: Exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: VHL_2 (tumor ID)

KindredID: 2

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 25Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: N/A

KindredID: 198

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states: Germline, de novo

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: p.W117Cfs*42 (c.351del)

LegacyVariant: N/A

CaseProblemVariantFreeText: paper states c.350delG which automaps to NM_000551.3:c.351delG

ClinVarID: 223197 https://www.ncbi.nlm.nih.gov/clinvar/variation/223197/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: W117fs (c.351del)

MultipleGeneVariants: N/A

ArticleReferenceSequence: NM_000551.3 (Standard)

GenotypingMethod: germline DNA analysis and PCR.

SamplingMethod: tumor tissue

GroupID/ KindredID: 19 / S 1

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

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

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

GroupHPOFreeText: Both (2) patients had RCC, 1 had hemangioblastomas and 1 had retinal capillary hemangioma. These phenotypes couldn’t be paired as it was not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

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).

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

GroupID: 35

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: N/A

SupplementalData: N/A

Variant: p.P154P (c.462A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA16621934 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.462A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P154= (c.462A>C)

MultipleGeneVariants: N/A

GroupID: 43

DiseaseAssertion: VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 8 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 3 members are stated to have retinal HBs. Other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: the other 5 patients are said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 31

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.Q132P (c.395A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496063 https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q132P (c.395A>C)

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

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

GroupID: 3003

DiseaseAssertion: assumed VHL

GroupSize: 27

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 27 family members recorded with this mutation.

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

GroupHPOFreeText: 11/27 members had retinal angioma (hemangioma), 9 had CNS hemangioblastoma, and 5 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 1 3003NCI); 9829911

SupplementalData: N/A

Variant: p.S168Ifs*5 (c.502_503insTTGTTCGT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.239fs (c.715insTTGTTCGT)

ClinVarID: N/A

CAID: CA2573051075 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051075

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: S168fs (c.502_503insTTGTTCGT)

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: 3568

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 5 family members recorded with this mutation.

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

GroupHPOFreeText: 1 member stated with an angioma (retinal hemangioma), 2 members have CNS hemangioblastoma, 4 with RCC.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 19464396

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.P86L (c.470C>T)

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

CAID: CA020186 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3760

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.Y112* (c.336C>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Y183* (c.549C>A)

ClinVarID: N/A

CAID: CA16602183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.336C%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y112* (c.336C>A)

MultipleGeneVariants: N/A

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

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This mutation was found in 2 Croatian, VHL type 1 family members (family VHL 26). Both have hemangioblastomas of the central nervous system, one has renal cysts, and one with pancreatic cysts.

The authors report this as an AF010238.1:c.443insTCT mutation at codon 77 (insertion Ser). This does not match the associating c. and p. - NM_000551.3:c.230_231insTCT matches Cys77_Asn78insLeu., while c.231_232insTCT (p.Cys77_Asn78insSer) would give the ins Ser the authors write, however this doesn’t match the p.. Without confirmation from authors no assumption could be made.

GroupID/ KindredID: VHL 51

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 6 patients with the given mutation belonging to VHL family 51

GroupPresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, Papillary cystadenoma of the epididymis)

GroupHPOFreeText: CNS hemangioblastomas found in all 6 members of this cohort, and epididimal cystadenomas found in 4 members.

GroupNotHPOs: GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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: CA020131 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.233A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: III-6

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father, the proband (II-4) carried the VHL mutation and presented with clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, and renal cysts. The patient's brother (III-7) carried the mutation but was asymptomatic. The patient's grandmother (I-2) died as a result of pancreatic cancer. His paternal aunt (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another paternal aunt (II-2) underwent surgery for breast cancer. See Figure 3 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Abdominal ultrasound examination of the patient revealed no abnormality.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F11

Case: Sex unknown, 32Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: Multiple lesions were found with the patient’s retinal hemangioma. Bilateral pheo. Age of onset is 32Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175N (c.523T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756226 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.523T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y175N (c.523T>A)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0000107; HP:0005584; HP:0010797; HP:0001737 (Renal cyst, Renal cell carcinoma, Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: Bilateral RCC and renal cysts, CNS hemangioblastoma, positive for pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.N78T (c.233A>C)

LegacyVariant: c.446A>C (N78T)

CaseProblemVariantFreeText: N/A

ClinVarID: 223168, https://www.ncbi.nlm.nih.gov/clinvar/variation/223168/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is declared as “c.446A>C (N78T)” by the authors, this was treated as a legacy variant and mapped to c.233A>C, N78T. This study found coexpression of Epo and EpoR in 11 RCCs and in 10 benign renal cysts in a spectrum of VHL renal disease suggesting that Epo/EpoR coexpression is present in both benign and malignant stages of renal neoplasia. Six benign cysts stained for Epo but not EpoR. The researchers detected loss of heterozygosity of a wild-type VHL allele in different RCCs with microsatellite markers, D3S1110 and D3S2452, flanking the VHL gene

MutationType: missense_variant;transition

CivicName: N78T (c.233A>C)

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: 6

KindredID: 6

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history but no further details were provided. CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

CasePresentingHPOs: HP:0009711; HP:0006748 (Retinal capillary hemangioma, Adrenal pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL type 2A. Right adrenal pheochromocytoma (41Y) and retinal angioma. No metastasis. Last follow-up 4 years after diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: c.547T>C

CaseProblemVariantFreeText: N/A

ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors report variant as “547, T to C”. Assumed to be reported in legacy nomenclature (AF010238.1 (Latif et al.)) and mapped to c.334T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: familial history of VHL disease

CasePresentingHPOs: HP:0030393; HP:0010797; HP:0001737 (endolymphatic sac tumor, hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: at 18Y experienced a sudden left hearing loss (MRI revealed hemangioblastomas of the temporal bone invading the otic capsule; operated on; the MTD of the endolymphatic sac tumor at diagnosis was 1.9 cm). The patient also developed pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Q (c.345C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496058 https://www.ncbi.nlm.nih.gov/clinvar/variation/496058/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: H115Q (c.345C>G)

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

PatientID: 22

KindredID: 4

Case: F, 8Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Asynchronous multifocal pheochromocytoma. 8Y at VHL diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 60

KindredID: 23

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

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 familial mutation (p.P97Afs*35, c.287_288insA) was confirmed in family #33, with 2 affected members that were both genetically confirmed for the mutation. A male proband (patient 99) was diagnosed with CNS hemangioblastoma at 37Y, retinal angioma at 20Y, renal cell carcinoma at 20Y, and multiple pancreatic cysts or tumours at 29Y. His brother (patient 100) was diagnosed with retinal angioma at 32Y, renal cell carcinoma at 43Y, and multiple pancreatic cysts or tumours at 43Y. 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 familial mutation was confirmed in family #48. Only the male proband (patient 128) was genetically confirmed with the mutation. He was diagnosed with CNS hemangioblastoma at 32Y, RCC at 38Y, pheochromocytoma at 40Y and multiple pancreatic lesions at 38Y. His father (patient 129) was diagnosed with RCC at 58Y and his daughter (patient 130) was diagnosed with CNS hemangioblastoma at 13Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: None

KindredID: 6

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: dilatation of the cerebral artery

FamilyInfo: None

CasePresentingHPOs: HP:0004944 (dilatation of the cerebral artery)

CaseHPOFreeText: Patient had an intracranial aneurysm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+8C>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 127830 https://www.ncbi.nlm.nih.gov/clinvar/variation/127830/

CAID: N/A

gnomAD: 0.0005055 https://gnomad.broadinstitute.org/variant/3-10188328-C-T

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Region (c.463+8C>T)

MultipleGeneVariants: N/A

PMID: 20034980

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 20

KindredID: MM

Case: M, 35Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0005584 (Pancreatic cysts, Renal cell carcinoma)

CaseHPOFreeText: RCC and multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0010797; HP:0030393; HP:0009711; HP:0002666 (Hemangioblastoma, Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID:1

KindredID: S3

Case: F, 35Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737, HP:0010797 (Pancreatic cysts, Hemangioblastoma)

CaseHPOFreeText: multi-cystic pancreatic lesions and CNS hemangioblastoma

CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666, HP:0030393 (Retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S72P (c.214T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223163 https://www.ncbi.nlm.nih.gov/clinvar/variation/223163/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: S72P(c.214T>C)

MultipleGeneVariants: N/A

“None of the novel mutations were represented in 120 alleles from normal subjects in the Brazilian population suggesting that these base changes are not common polymorphisms.”

GroupID: 11

DiseaseAssertion: VHL

GroupSize: 14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 14 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0002894; HP:0009711; HP:0010797; HP:0005584 (Neoplasm of the pancreas, Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma)

GroupHPOFreeText: CNS hemangioblastoma (7/14 affected members), renal carcinoma (1/14 affected members) and retinal angioma (2/14 affected members) and pancreatic cystadenoma (number of affected individuals not specified).

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130F (c.388G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: This variant was not found in 120 alleles from normal subjects in the Brazilian population.

MutationType: missense_variant;transversion

CivicName: V130F (c.388G>T)

MultipleGeneVariants: N/A

PMID: 23845641

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: IV-17

KindredID: 1

Case: M, 16Y0M, Iranian

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had a unilateral PCC at 14Y which was surgically removed at the time. Histopathology was benign, and there was no case of relapse or metastatic dissemination.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

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

GroupID: 333

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with the c.500G>A germline variant of the VHL gene. Member 9428 presented with mild renal disease. Member 13001 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP: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).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 10 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously reported individuals/families could alternatively correspond to family 262, 36 or 509.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

ArticleReferenceSequence: AF010238.1 (Legacy Variants- Latif et al.) and NM_000551.3

GenotypingMethod: PCR, SSCP and when abnormal mobility shift was observed, direct sequencing was performed. If no shift was detected or no mutation was found by sequencing, authors proceeded to Southern blotting for detection of large rearrangements.

SamplingMethod: peripheral blood

GroupID: 185

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family are reported as carrying the c.193T>C germline variant of the VHL gene. Member 9359 has unknown renal involvement. Member 9357 presented with mild renal disease. Member 1052 had no renal involvement. Member 3979 has moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP: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).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 2 patients with this mutation are reported but relation between patients is unknown.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

PMID: 15383938

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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)

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.

PatientID: 7

KindredID: 7

Case: F, 70Y0M, Taiwanese (East-Asian)

DiseaseAssertion: renal cell carcinoma

FamilyInfo: N/A

CohortInfo: 8 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs1642742 in VHL (c.*294G>A). All but one of these patients (7/8) also presented with the germline variant rs779805 (c.-195G>A) in VHL.

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

CaseHPOFreeText: She had stage IV clear cell renal cell carcinoma with metastasis

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21982469

SupplementalData: Yes - Additional file 1: Figure S1

Variant: c.*294G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 342407 https://www.ncbi.nlm.nih.gov/clinvar/variation/342407/

CAID: N/A

gnomAD: 0.5911 https://gnomad.broadinstitute.org/variant/3-10191943-G-A

VariantEvidence: LOH (G) of this mutation was found in the tumor tissue as well

MutationType: 3_prime_UTR_variant

CivicName: c.-195G>A AND c.*294G>A

MultipleGeneVariants: Somatic, VHL, c.-195G>A

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.

PatientID: 24

KindredID: 24

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Negative family history.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: a carotid body (paraganglioma) was reported with no other details.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

CaseProblemVariantFreeText: Variant is written in paper under p.Tyr152Ile. This is incorrect however is paired to a paper where this variant it described (PMID: 18031321) referencing Thr152Ile, so this was deduced.

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:T152I (c.455C>T)

MultipleGeneVariants: N/A

Twelve patients with hereditary non-SDHx head and neck paragangliomas were analyzed. Eleven of the 12 patients were found to carry germline mutations in the VHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The 39 year old female proband was found to harbour the p.Y156C (c.467A>G) mutation of the VHL gene. She presented with recent onset of hypertension and was diagnosed with a right pheochromocytoma. At age 36, a suspected left pheochromocytoma was noted by CT and increased urinary metanephrines was confirmed at age 39 by MIBG scintigraphy. This imaging showed in addition an uptake located in the neck. MRI confirmed a left adrenal tumor and a left 2cm vagal paraganglioma that was removed and confirmed histopathologically. No other tumor of the VHL spectrum was discovered. Three of her four sons were found to carry the mutation and all underwent clinical screening. One of these sons presented with a 2.4cm abdominal paraganglioma.

PatientID: 11

KindredID: 11

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: There was said to be, at the time, no affected relatives

CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0006476; HP:0006880; HP:0009711; HP:0000618; HP:0010797 (adrenal pheochorocytoma, paraganglioma, abnormality of the pancreatic islet cells, cerebellar hemangioblastoma, retinal capillary hemangioblastoma, blindness, hemangioblastoma)

CaseHPOFreeText: At 8Y, (in 1978), she was operated for a right pheochromocytoma; at age 13 for a contralateral pheochromocytoma; at age 15, for a 4-cm mass at the neck was diagnosed by selective arteriography as a carotid paraganglioma. The patient was then operated twice for cerebellar hemangioblastoma at age 22, leading to the diagnosis of VHL disease. At age 27, the patient was operated again for a retrocaval pheochromocytoma and for islet cell tumors. The patient was also repeatedly treated for bilateral retinal hemangioblastomas leading to blindness at age 32. At age 36, again a pheochromocytoma was removed

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: p.T157I

CaseProblemVariantFreeText: The publication only provides the p., the mutation was able to be deduced to p.T157I (c.470C>T)

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A