PatientID: None

KindredID: 67

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198Gfs*57 (c.592_593del)

LegacyVariant: c.805_806del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795185, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.592_593del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_framshift_variant

CivicName: L198Gfs*57 (c.592_593del)

MultipleGeneVariants: N/A

GroupID: 9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 3 individuals from a single family (ID 9).

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0001732 (Retinal capillary hemangioma, Hemangioblastoma, Abnormality of the pancreas)

GroupHPOFreeText: CNS hemangioblastoma (3/3), retinal angioma (3/3) and pancreatic tumor or cyst (unspecified) (2/3).

GroupNotHPOs: HP:0005584 (Renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

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

LegacyVariant: c.446A>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N78T (c.233A>C)

MultipleGeneVariants: N/A

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The S80Ifs*79 (c.239del) germline mutation was found in a VHL type 1 patient presenting with CNS hemangioblastoma, renal cell carcinoma and retinal angioma (family ID 22). This family was previously reported in PMID 8634692.

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The T157I (c.470C>T) missense mutation was found in 2 VHL family members (family ID 69). Both had hemangioblastomas of the central nervous system and pancreatic cysts or tumor (unspecified). 1/2 patients had renal cell carcinoma and 1/2 patients had pheochromocytoma.

PatientID: 93

KindredID: 93

Case: M, 36Y0M, Chinese (East Asian)

DiseaseAssertion: Pheochromocytoma

FamilyInfo: Positive family history.

CasePresentingHPOs: Pheochromocytoma (HP:0002666)

CaseHPOFreeText: Pheochromocytoma, with a biggest tumor size of 6.5cm. Age of onset at 10Y and diagnosis at 13Y. 36 years later they were confirmed with a genetic mutation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

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: Described as a pathogenic variant, according to the ACMG guidelines at the time of publication.

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

314 Chinese patients with Pheochromocytoma/paraganglioma (PPGL) from Peking Union Medical College Hospital, China, were included in this study for germline profiling. The majority of patients underwent surgery and were histopathologically diagnosed with PPGL. For patients who had an unresectable or metastatic tumor, PPGL diagnosis was determined based on clinical features (headache, palpitations, sweating, etc). Genomic DNA was extracted from peripheral blood of all 314 PPGL patients, and detect potential variants in 12 known genes associated with hereditary PPGL (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) using next-generation and Sanger sequencing. Germline variants were detected in 29% of the 314 PPGL patients. Patient #84 is a male PPGL patient diagnosed with bilateral pheochromocytoma at age 12. Germline genetic testing revealed a missense V87E(c.260T>A) variant in exon 1 of the VHL gene. Patient 84 has no family history of PPGL.

Of 246 patients affected with Von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene were determined from sequencing peripheral blood using PCR, SSCP (single-strand conformation polymorphism), and Southern Blotting. Family 5958, 6105, 3493, 5143, 6106 and 5068 were found with p.Arg167Gln mutations in the VHL gene (legacy notation c.713G>A converted to NM_000551.3). Family 5958: 5/5 had pheochromocytoma, 1/5 had renal cell carcinoma, 1/5 had CNS hemangioblastoma, 1/5 had retinal angiomas, 0/5 had cysts. Family 6105: 3/6 had pheochromocytoma, 4/6 had renal cell carcinoma, 3/6 had CNS hemangioblastoma, 2/6 had retinal angiomas, 1/6 had cysts. Family 3493: 2/2 had pheochromocytoma, 2/2 had renal cell carcinoma, 2/2 had CNS hemangioblastoma, 2/2 had retinal angiomas, 1/2 had cysts and pancreatic neuroendocrine tumor was also found in the family (number of affected members with PNET was not described). Family 3493 has been reported previously in whole or in part in PMID 7728151. Family 5143: 1/1 had pheochromocytoma, 1/1 had renal cell carcinoma, and 1/1 had CNS hemangioblastoma. Family 6106: 1/2 had pheochromocytoma, 2/2 had renal cell carcinoma, 0/2 had CNS hemangioblastoma, 1/2 had retinal angiomas, 2/2 had cysts and pancreatic neuroendocrine tumor was also found in the family (number of affected members with PNET was not described). Family 5068: 3/3 had pheochromocytoma, 0/3 had renal cell carcinoma, 1/3 had CNS hemangioblastoma, 2/3 had retinal angiomas, 2/3 had cysts and pancreatic neuroendocrine tumor was also found in the family (number of affected members with PNET was not described). Individual patient phenotype-genotype was not described in the paper.

PatientID: None

KindredID: 4589

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: Diagnosed with VHL Type 2B.

CaseNotHPOs: HP:0010797; HP:0005584 (Hemangioblastoma; Renal cell carcinoma)

CaseNotHPOFreeText: No CNS hemangioblastoma or RCC presentations.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162F (c.485G>T)

LegacyVariant: c.698G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 43604, https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191492-G-T?dataset=gnomad_r2_1

VariantEvidence: Variant reported as 689, G to T (Cys to Phe), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.485G>T, p.Cys162Phe (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: C162F (c.485G>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 7

Case: F, 62Y0M, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: Patient had family history of VHL disease. Patient’s nephew presented with renal cell carcinoma at 30, patient's sister/brother presented with a hemangioblastoma at age 39 and then retinal capillary hemangioma, renal cell carcinoma, and abnormality of the pancreas at age 57. Patient’s brother presented with retinal hemangioma at age 25 and renal cell carcinoma at age 54. All three of these family members were genetically tested and possessed the same mutation. Patient’s other brother presented with a hemangioblastoma at age 35 but died before diagnosis and genetic testing.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient presented with hemangioblastoma at age 40

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0006770, HP:0001732 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, clear cell renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178R (c.533T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625261, https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L178R (c.533T>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 12

Case: F, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's son was confirmed to have the genetic mutation and presented with pheochromocytoma, renal cell carcinoma, and abnormality of the pancreas.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 13

Case: Sex Unknown, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's mother had a hemangioblastoma at age 40 but was not genetically confirmed to have the mutation.

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

CaseHPOFreeText: The patient presented with cysts or tumours of the pancreas, renal cell carcinoma, and retinal angioma at age 34.

CaseNotHPOs: HP:0010797, HP:0002666 (hemangioblastoma, pheochromocytoma)

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

SupplementalData: N/A

Variant:p.V155Dfs*17(c.464_468delTGTAT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2499306942 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306942&fbclid=IwAR1k8AeHEqS_dwb3ClO4W8AWqBs2tf0malEPJ2nbl-bl7ZkgNC3jeWbaDds

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName:V155fs(c.464_468delTGTAT)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: Sex Unknown, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's father had a hemangioblastoma of the central nervous system at age 42. He was deceased before diagnosis could occur.

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

CaseHPOFreeText: The patient presented with hemangioblastoma and renal cell carcinoma at age 29. At age 33, the patient presented with pancreatic cysts or tumours.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0009715 (retinal capillary hemangioma, pheochromocytoma, Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:29330336

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: stop_gained

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

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 mutation was recorded in the paper with AF010238.1: c.676+2C>T. This translates to NM_000551.3:c.463+2C>T, however no C exists at c.463. As no Cytosine is found around the area of c.463, will assume the authors wrote this backwards and correct variant is c.463+2T>C, however NO confirmation was received from the authors. It was found in 1 patient with hemangioblastomas of the central nervous system. Any family information is unknown. No other phenotypes described.

PMID: 9209471

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There were 3 patients reported with the p.L85P (c.254T>C) mutation. All 3 members presented with retinal hemangiomas, while no other clinical manifestations were discussed. Additionally, no family information was provided.

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renalcell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. Out of the 3 patients with a synonymous p.E31= (c.93G>A) mutation, 33% (1/3) of individuals had RH and 67% (2/3) did not. No family information was provided.

In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma. Deletions, nonsense, and frameshift mutations were more frequently found in families without pheochromocytoma. Large deletions and mutations predicted to cause truncated protein were associated with lower risk pheochromocytoma. The mutation of p.S65W (c.194C>G) was referred to in the paper by c.407C>G due to a difference in transcript sequence. This missense mutation was found in one of the VHL families (family ID 39).

PatientID: 1

KindredID: V5PG

Case: Age unknown, sex unknown, Italian

DiseaseAssertion: assumed VHL

FamilyInfo: 2 twin patients belonging to family V5PG were examined. Both with hemangioblastomas and 1 also with retinal hemangioblastomas. Sequencing of patients’ DNA and paternity and monozygosity of the 2 twins was ascertained, revealed a de novo missense mutation.

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 446 (78) A>G (N78S)

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

PMID: 16261628

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 68 (Cousin)

KindredID: 18

Case: F, 66Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

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

CaseHPOFreeText: This patient presented with retinal angioma (22Y). Age of diagnosis for renal cell carcinoma is unknown.

CaseNotHPOs: HP:0000077; HP:0001732; HP:0002666; HP:0010797 (Abnormality of the kidney, Abnormality of the pancreas, Pheochromocytoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

20 vHL families were retrospectively identified in SickKids Genetics and Cancer Genetics Program SHIRE genetics database, with data entered between 30 August 1984 and 8 August 2016. Family 12 had one patient (proband, male, ID 1) confirmed with the c.406T>C (mapped to 193T>C after consultation with SickKids) missense mutation. The proband's age of onset was 27Y and his last known age is 57Y. The proband had hemangioblastoma (37Y); retinal angioma (27Y); renal cysts/tumors (28Y); pancreatic cysts/tumors (28Y). The proband's father (ID 8) was also diagnosed with RCC at 46Y and died at 47Y, although he was never genetically confirmed with the mutation.

PatientID: 139 (Second cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: This patient presented with retinal angioma (16Y). Age of diagnosis of pheochromocytoma and renal cell carcinoma is unknown.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None (XI)

KindredID: 7

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001737; HP:0005584 (hemangioblastoma, renal cyst, pancreatic cysts, renal cell carcinoma)

CaseHPOFreeText: initially thought to be asymptomatic, first screening showed 1 HB; 5 year follow up showed +RC, PC, RCC

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. 4 (3 adults and 1 child) members from family 1 were tested positive with p.F76del mutation. 3 adult patients were affected at initial screening. 1 child was asymptomatic both at initial screening and at last follow up. ACMG evidence codes: 'PP4' because the patients' family history are highly specific for a disease with single genetic etiology.

GroupID/ KindredID: 30CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 30CE. 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.Q132* (c.394C>T)

LegacyVariant: p.Q132* (c.607C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/

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: Q132* (c.394C>T)

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 (L178P (c.533T>C)) was taken from multiple databases including: the National Cancer Institute database, the Cambridge, Department of Pathology database, the Department of Uroglogy, Yokohama database. As reported in Table 3, it was found in VHL families without pheochromocytoma, and with renal cell carcinoma) with an unknown number of members belonging to Family IDs: 3314NCI, 44CA, 4419NCI, 4403NCI, and 34Y0. Reported in Table 4, which describes VHL families with pheochromocytoma, was Family ID 3786NCI. It was reported in the paper as c.746T>C due to a difference in transcript reference. Other phenotypes are likely, however not detailed here. Later publications reference this cohort as being reported in PMID: 7728151.

GroupID/ KindredID: 8BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to family ID: Family 8BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L135* (c.404T>A)

LegacyVariant: p.L135* (c.617T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754021 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T>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: L135* (c.404T>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 48CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 48CE. 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: (c.464-1G>A)

LegacyVariant: Splice (c.677-1G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

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: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 3

KindredID: II

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: c.553+1G>A

ClinVarID: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: N/A

gnomAD: N/A

VariantEvidence: Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.

MutationType: splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

PatientID: proband (F2-II-11)

KindredID: 2

Case: F, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patients son (F2-III-9) was a 9-year old male patient with a right adrenal pheochromocytoma. The son later presented with a left adrenal pheochromocytoma at 17-years-old. The patients niece (F2-III-4) was a 33 year old female with bilateral pheochromocytoma. The patients brother (F2-II-3) succumbed to hypertensive intracerebral hemorrhage 21 years prior to this study.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: presented with paroxysmal hypertension (180–210/100–120 mmHg), headache, palpitations and hyperhidrosis in 1985 at the age of 18. US scans showed an isolated mass in the right adrenal gland.

CaseNotHPOs: HP:0005584, HP:0000107, HP:0010797 (renal cell carcinoma, renal cyst, hemangioblastoma)

CaseNotHPOFreeText: no other systematic tumors, including CNS hemangioblastomas, renal cysts or renal cell carcinoma, were identified

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: CA020413

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

KindredID: 152

GroupID: 47

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.152 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: N/A

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.R167Q (c.500G>A)

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

KindredID: 136

GroupID: 21

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.136 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: N/A

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.R113* (c.337C>T)

LegacyVariant: c.550C>T (p.R184*)

CaseProblemVariantFreeText: N/A

ClinVarID: 220414, https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113* (c.337C>T)

MultipleGeneVariants: N/A

KindredID: 79

GroupID: 51

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 79 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I180V (c.538A>G)

LegacyVariant: p.I251V (c.751A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 161401, https://www.ncbi.nlm.nih.gov/clinvar/variation/161401/

CAID: N/A

gnomAD: 0.00001061, https://gnomad.broadinstitute.org/variant/3-10191545-A-G?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: I180V (c.538A>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 43

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Reported as familial VHL - no further information provided

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584; HP:0000107 (hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 deletion

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.430G>T) was detected in 1 member of family 19. The patient was adopted, hence the family history is not available. The patient presented with multiple retinal capillary hemangioma.

PatientID: 161

KindredID: 62

Case: F, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's daughter presented with a CNS hemangioblastoma and multiple pancreatic cysts and tumors at the age of 14.

CasePresentingHPOs: HP:0005584; HP:0002666; HP:0010797; HP:0001737; HP:0001732 (Renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 28, and a renal cell carcinoma, multiple pancreatic cysts/tumors, and a pheochromocytoma at age 41.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

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.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

CivicName: R161* (c.481C>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 familial mutation was confirmed in family #36, in which the proband was confirmed for the genetic mutation, but his mother passed away before genetic testing. A male proband was diagnosed with CNS hemangioblastoma and retinal angioma at 18Y. His mother was diagnosed with CNS hemangioblastoma and retinal angioma at 29Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 195

KindredID: 75

Case: M, 32Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 32.

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

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.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 143

KindredID: 52

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's nephew (son of sister 1) was asymptomatic at the time of analysis.

CaseNotHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732; HP:0002666; HP:0009711 ((Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, Retinal capillary hemangioma)

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.464-1G>C

LegacyVariant: N/A

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: 179

KindredID: 70

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 179) had a daughter (patient 180) who was confirmed with the mutation, and present4ed with a retinal angioma and multiple pancreatic cysts/tumors at 17. The proband also has three family members who were unconfirmed with the mutation (passed away before diagnosis): patient 181 (proband's brother) had a CNS hemangioblastoma at 17, patient 182 (proband's father) had a CNS hemangioblastoma at 49, renal cell carcinoma and multiple pancreatic cysts/tumors at 56, and patient 183 (proband's uncle) had a CNS hemangioblastoma at 32 and a retinal angioma at 30.

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

CaseHPOFreeText: The proband presented with a renal cell carcinoma at 44, and multiple pancreatic cysts/tumors at 28.

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

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.C162* (c.486C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223226; https://www.ncbi.nlm.nih.gov/clinvar/variation/223226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162* (c.486C>A)

MultipleGeneVariants: N/A

PatientID: 150

KindredID: 55

Case: M, 17Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 150) has a father (patient 151) who was also confirmed with this germline mutation, and presented at 22 with a CNS hemangioblastoma and 28 with renal cell carcinoma. The proband also has a grandmother (patient 153) who presented with a CNS hemangioblastoma at 43, but who passed away before diagnosis/ genetic testing.

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

CaseHPOFreeText: The proband presented at age 14 with a CNS hemangioblastoma, and age 17 with multiple pancretic cysts/tumors.

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

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.I151S (c.452T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223215, https://www.ncbi.nlm.nih.gov/clinvar/variation/223215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: I151S (c.452T>G)

MultipleGeneVariants: N/A

PatientID: 215

KindredID: 80

Case: F, 14Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's brother (the proband) and nephew both had the same mutation. Their brother had a CNS hemangioblastoma at 26. Their nephew had a retinal angioma at 26, and a pheochromocytoma at 31. Their mother had renal cell carcinoma at 56, however no genotyping information is available for her.

CasePresentingHPOs: ; HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 14.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0010797; HP:0009711 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma, Retinal Capillary Hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 248

KindredID: 95

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 246) has an asymptomatic daughter (patient 247), a sister (patient 248) with renal cell carcinoma at age 44, and an asymptomatic nephew (patient 249) (son of sister), all confirmed with the mutation.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband's sister presented with renal cell carcinoma at age 44.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort 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: Exon 1 Deletion (c.1-?_340+?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 Deletion

MultipleGeneVariants: N/A

A 40-year old Caucasian female from Slovenia was found to have a missense germline mutation in VHL, c.452T>A (p.Ile151Asn). The patients extraneuraxial hemangioblastoma tissue was also tested for somatic mutations in the VHL gene and a somatic mutation c.500G>A (p.R167Q) was identified. PCR amplification was performed searching for point mutation in the entire VHL coding sequence and promoter region, including exon-intron boundaries. Amplification was performed in a Gene Amp PCR System 9700 (Perkin Elmer). When mutations were detected in DNA from tumor samples, it was searched for in the corresponding peripheral blood DNA in order to identify germline mutations. The patient was found to have two extraneuraxial hemangioblastomas, the locations of these tumors included intra/paraspinal (extradural) and the nerve roots. Her past medical history included  cerebellar hemangioblastomas, clear cell renal cell carcinoma, an adrenal pheochromocytoma, and cysts in both the  kidney and  pancreas. The patient died of VHDL after 17 months after testing when followed up. There was no known family history.

This paper analysed high-grade ccRCC and paired normal tissues to identify somatically-acquired SNPs and indels with Sanger sequencing and NGS. 79% of the reported ccRCC tumors were somatically acquired. Additionally, germline mutations for VHL were described in Supplementary Table 1. A VHL germline mutation described was found through normal kidney tissue. This sample (ID-2368) was in a clear cell RCC individual (61Y, Male) with the germline VHL mutation: p.E21A (c.62A>C). He was a non smoker with no family history. No further phenotypic information was provided. Additionally, a somatic PBRM1 mutation (c.2703delT) was found in this patient.

PMID: 10533030

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 25

KindredID: 1

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 1 was mentioned (Patient: 33). This patient was found to have a pancreatic endocrine tumour, pheochromocytoma and renal cell carcinoma.

CasePresentingHPOs: HP:0030405; HP:0002666 (pancreatic endocrine tumour, pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

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

Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. Patient no. 34 from family 94 had a missense mutation in the VHL gene (c.407T>C) and presented with pancreatic endocrine tumour and renal carcinoma. The patient's phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).

PatientID: III-11

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transversion mutation was found and confirmed in 4 patients (II-2, III-2, III-6, III-10, III-11) and 3 carriers (III-3, III-9, III-14). At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. Could be assumed and deduced their genetics due to pedigree showing future linear relations of this mutation all in generation III.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S168T (c.503G>C)

LegacyVariant: p.S168T (c.716G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.503G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient had two children with the same genetic mutation. Son presented with bilateral pheochromocytoma (13Y) and endolymphatic sac tumor (19Y). Daughter was asymptomatic.

CasePresentingHPOs: HP:0005584; HP:0002666; HP:0001945; HP:0000790 (Renal cell carcinoma, Pheochromocytoma, Fever, Hematuria)

CaseHPOFreeText: A 48Y man presented with loin pain, pyrexia and haematuria. He was initially thought to have pyelonephritis but a renal ultrasound scan showed a right renal mass. The CT scan and the MRI confirmed the finding of a large right renal mass invading the renal vein and also identified bilateral adrenal masses. hoarse voice due to a mass impinging on the laryngeal nerves. A diagnosis of VHL presenting with a metastatic right RCC and bilateral pheochromocytomas was made. Despite chemotherapy for the metastatic RCC, he died 1 year after diagnosis.

CaseNotHPOs: HP:0000822 (Hypertension)

CaseNotHPOFreeText: He was normotensive at 48Y.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 58

Case: F, 44Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: No familial antecedents or known familial tumors.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880; HP:0006770 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 14722919

SupplementalData: N/A

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline HSPC300 retention. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

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. 3 patients were found to have the above mutation (c.488T>A). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other 2 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: 26B

Case: Sex, Age, Ethnicity unknown

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.

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: HP:0030405 (pancreatic endocrine tumor)

CasePreviousTesting: Patient was negatively tested for islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

PreviouslyPublished: N/A

SupplementalData: N/A

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: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 25

KindredID: 4

Case: F, 12Y0M, 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: Multifocal pheochromocytoma. 12Y 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: III-1

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient’s uncle (II-1) was found to harbor the same germline mutation the patient harbored and had bilateral adrenal pheochromocytoma at 14Y. The patient’s aunt (II-2) was found to harbor the same germline mutation the patient harbored and had left adrenal pheochromocytoma at 10Y. The same germline missense mutation was found in the patient’s mother (II-4) who had right adrenal pheochromocytoma. The grandfather was not available for genetic testing because he had died, apparently secondary to a hypertensive crisis. The five other family members which underwent genetic testing did not have the mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F(c.496G>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: Exons 1, 2, and 3 of the VHL gene were amplified by PCR. Amplification was performed with 100 ng of genomic DNA in a 25 µL reaction containing 20 pM of each primer, 10 X buffer (50 mM KCl, 20 mM Tris-HCl, pH 8.4), 1.0 mM MgCl2, 0.2 mM each of dNTP, and 1.25 U Taq DNA Polymerase (Gibco-BRL). A Genetic Analyzer 3100 Sequencer (Applied Biosystem, Foster City, CA, USA) was used after PCR amplification.

SamplingMethod: Peripheral blood

PatientID: 2

KindredID: 2

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history. He was offered clinical surveillance due to a family history of known VHL and genetic testing that revealed him positive for the family-specific VHL mutation. The father and two brothers have been treated for multiple retinal, cerebellar, and spinal cord hemangioblastomas, although it did not clearly state whether they all carried the mutation.

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

CasePresentingHPOs: HP:0040277; HP:0002668; HP:0001737; HP:0006770 (neoplasm of the pituitary gland, paraganglioma, pancreatic cyst, clear cell renal cell carcinoma)

CaseHPOFreeText: Originally asymptomatic at age 29Y, clinical surveillance revealed a pituitary tumor. At age 34, he had painful swelling on left neck where a mass was found, and CT disclosed a left carotid body tumor (paraganglioma)(later resected). At age 41, multiple pancreatic cysts were detected and a left kidney cancer that was resected (histologically showed clear cell carcinoma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L135 (c.404T>A) OR p.L135 (c.404T>G)

CaseProblemVariantFreeText: As the publication only provides the p., the exact mutation is not known. p.L135* can translate to either c.404T>A or c.404T>G

LegacyVariant: N/A

ClinVarID:

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: N/A (son 2)

KindredID: 5

Case: M, 27Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: His mother was confirmed with the mutation, and various manifestations of VHL. His two brothers also carried the mutation, one with adrenal pheochromocytomas as well. His grandmother and great uncle passed away likely due to VHL complications.

CasePresentingHPOs: HP:0009711; HP:0009713 (retinal capillary hemangioma, spinal hemangioblastoma)

CaseHPOFreeText: At 27Y screening showed an asymptomatic retinal and spinal hemangioblastoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R107H (c.320G>A)

LegacyVariant: p.R107H

CaseProblemVariantFreeText: As the publication only provides the p., the mutation was deduced to p.R107H (c.320G>A)

ClinVarID: 223184 https://www.ncbi.nlm.nih.gov/clinvar/variation/223184/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R107H (c.320G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her family history was concerning for pheochromocytoma and renal cell carcinoma in her father and a paternal aunt, and a paternal grandmother with history of brain tumor. All of these individuals were deceased. No genetic testing had been performed on any of her affected relatives.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: MRI scan ascertained diagnosis of bilateral pheochromocytoma (which preceded by at least 5 years). The pheo and resulting in recurrent episodes of malignant hypertension and intrauterine fetal demise led to the appropriate peripartum diagnosis of VHL syndrome

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A - not stated

SamplingMethod: N/A - not stated

GroupID/ KindredID: 16

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

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

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

GroupHPOFreeText: 4 patients were tallied with a retinal capillary hemangiomas, and 4 with cHemangioblastomas. These phenotypes couldn’t be paired as it was not clear with each member.

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: None of the patients were recorded to have RCC

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162Y (c.485G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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/ KindredID: 8

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This mutation (p.N78S (c.233A>G)) was found in Family No. 8 with 1 member affected. Germline de novo mutations confirmed by analysis of parents’ DNA. Germline mutations (of 233A>G substitution) were not detected in DNA extracted from blood leucocytes of the parents.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

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

GroupID/ KindredID: 27

PatientID: I

Case: 34Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 27 consisted of 2 members; One other member (21Y) was found to be asymptomatic at 20Y, but later observed with a single cerebellar HAB

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0000107 (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cyst)

CaseHPOFreeText: Patient was diagnosed with multiple spinal HABs, a single cerebellar HAB diagnosed at 27Y, bilateral retinal HABs, and renal cysts

CaseNotHPOs: HP:0009711; HP:0005584 (retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

GroupID: 11

DiseaseAssertion: VHL

Group size: 2

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. From this family, 2 individuals were suspected of VHL disease, but none developed RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: None of the VHL patients presented with retinal capillary hemangioma.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: Chr3(GRCh37): g.10191507G>A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 4485

DiseaseAssertion: assumed VHL

GroupSize: 51

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 51 family members recorded with this mutation.

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

GroupHPOFreeText: 25 of the 51 family members had an angioma (retinal hemangioma), 29 had RCC, 32 members had CNS hemangioblastoma, and 1 had a pheochromocytoma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (confirmed Zbar 1996 type 2 family 4485NCI)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L158P (c.686T>C)

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

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 in-frame deletion was found in a VHL type 1 family of 6 individuals (family ID 3177), using PCR and SSCP sequencing. The mutation of c.244del was referred to in the paper by c.457delCGCGTCGTC due to a difference in transcript sequence. Four of 6 individuals were identified with angiomas and 3 had CNS hemangioblastomas.

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 1 VHL type 1 family member (family ID 4401), using PCR and SSCP sequencing. The mutation of c.333C>G was referred to in the paper by c.546C>G due to a difference in transcript sequence. The member had only CNS hemangioblastomas. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4).

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. The S65W(c.194C>G) mutation was detected in the patients, referred to in the paper by c.407C>G due to a difference in transcript sequence. This missense mutation was found in a VHL type 1 family of four individuals (family ID 4325). Three of 4 individuals were identified with retinal hemangioblastomas and one with CNS hemangioblastomas.

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. The p.P86L (c.257C>T) mutation was detected in the patients, referred to in the paper by c.470C>T due to a difference in transcript sequence. This missense mutation was found in two VHL type 1 families of 12 individuals altogether (family IDs 2612 and 3568). Nine of 12 individuals were identified with CNS hemangioblastomas, 6 with retinal hemangioblastomas, and 6 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). Relevant HPO terms: hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma.

PatientID: III:8

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: One of the proband's maternal cousins was a healthy individual that was demonstrated to carry the same mutation, as revealed by Sanger sequencing: III:8, female. A second cousin, a 28 year old male (the proband III:2), was also found to have the same mutation and had a hemangioblastoma. A further five affected members of the family had previously died from VHL syndrome, including III:8's father (II:5), paternal grandfather (I:1), an uncle (II:3) and aunt (II:2) and a sister (III:10). These deceased family members had not previously been tested for mutations in the VHL gene. Pedigree: see Figure 1.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: All members of the family were examined by two experienced surgeons. Diagnoses of VHL syndrome were determined via investigation of medical histories and performance of physical examinations, including a complete neurological examination and brain magnetic resonance imaging (MRI)

CasePreviousTesting: N/A

PreviouslyPublished: NA

SupplementalData: NA

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

ClinVar: 496057 https://www.ncbi.nlm.nih.gov/clinvar/variation/496057/

CAID:N/A

gnomAD: N/A

VariantEvidence: RNA extracted from peripheral blood samples obtained from patients in the pedigree and the healthy controls. No significant difference in the expression of pVHL was demonstrated between the mutated and wild type cDNA, as demonstrated by RT-sqPCR analysis.

MutationType: missense_variant;transversion

CivicName: H115Q (c.345C>A)

MultipleGeneVariants: N/A

PatientID: proband (III:2)

KindredID: 1

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Two of the proband's maternal cousins were healthy individuals that were demonstrated to carry the same mutation, as revealed by Sanger sequencing: III:4, male, and III:8, female as seen in the pedigree from Figure 1. A further five affected members of the family had previously died from this syndrome, including the proband's mother (II:2), maternal grandfather (I:1), two uncles (II:3 and II:5), and a cousin (III:10). These deceased family members had not previously been tested for mutations in the VHL gene. Pedigree: see Figure 1.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: A cyst and a nodule were revealed via brain MRI. The cyst was demonstrated to be a hemangioblastoma tumor following surgical excision

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: NA

SupplementalData: NA

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

ClinVar: 496057 https://www.ncbi.nlm.nih.gov/clinvar/variation/496057/

CAID:N/A

gnomAD: N/A

VariantEvidence: RNA extracted from peripheral blood samples obtained from patients in the pedigree and the healthy controls. No significant difference in the expression of pVHL was demonstrated between the mutated and wild type cDNA, as demonstrated by RT-sqPCR analysis.

MutationType: missense_variant;transversion

CivicName: H115Q (c.345C>A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Her child had polycythemia and had two VHL gene mutations; one he obtained from his father and another he obtained from this patient, the mother. The entire family had normal sensitivity of erythroid progenitors to Epo.

CasePresentingHPOs: N/A

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: CA020510 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.598C%3ET

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

VariantEvidence: The patient is heterozygous for the 598C>T mutation.

MutationType: missense_variant;transition

CivicName: R200W (c.598C>T)

MultipleGeneVariants: N/A

DNA samples of 20 members from the Chinese family with non-syndromic PCCs and 41 patients with apparently sporadic pheochromocytoma were analyzed by polymerase chain reaction and direct sequencing, confirmed by Taqman probe. A 22 year old Chinese male patient (Proband 7) presenting with unilateral pheochromocytoma as well as a 29 year old male patient (Proband 8) presenting with unilateral PCC diagnosed at 29Y and bilateral renal cysts. Genetic testing confirmed a familial frameshift mutation at 623insTTTTGTtG of the VHL gene. VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3 Proband 7 has a father (Carrier 11), mother (Carrier 13) and a sister (Carrier 12) with the same mutation, however the father and sister are asymptomatic, while the mother also presents with unilateral pheochromocytoma. Family history of Proband 8 was not specified.

PatientID: Carrier 3 (son to proband 2)

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 12

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 3 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: 2 members had CNS hemangioblastomas, 1 has retinal angiomas, 1 had RCC, and 1 had a pancreatic abnormality

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No family members appeared to have the above manifestation.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Q96* (c.499C>T)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PMID: 18474773

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 32241160

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

A case report of a Jewish-Yemenite individual with Von Hippel Lindau disease. This individual belongs to a large, four generation Jewish-Yemenite family, although there is no mention of the number of affected individuals. The above mutation L178Q (c.533T>A), referred to in the paper as c.746T>A due to a difference in transcript sequence, was identified in this patient by denaturing gradient gel electrophoresis who presented with pheochromocytoma and CNS hemangioblastoma. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology.

PatientID: 15

KindredID: 9

Case: F, 59Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another individual (patient 16) from the same family was reported but their relationship to patient 15 was not indicated. This individual had VHL disease but the types of tumours they had were not specified.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient has VHL disease with CNS hemangioblstoma. She also had other tumours, but specific types of tumours were not indicated.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have CNS hemangioblastoma or Retinal capillary hemangiomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: 7

KindredID: 3

Case: M, 7Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: A family pedigree is provided in figure 1. Both the father and sister of patient 7 were found to have the same mutation. His father had retinal, cerebellar and spinal hemangioblastomas, as well as retinal detachment. His 10-year-old sister did not have any known tumours.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have retinal capillary hemangioma or other known tumours.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Gender Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Renal cell carcinoma

FamilyInfo: The paper stated that the patient had family members with the same mutation.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.V170D(c.722T>A)

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D(c.509T>A)

MultipleGeneVariants: N/A

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France (c.525C>A).

GroupID: None

DiseaseAssertion: VHL

GroupSize: 15 GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: Dutch GroupAgeRange: 16-71

GroupInfo: 15 out of 82 individuals were grouped together based on all having the c.509T>A of the VHL gene. This individual was classified as 2a/b meaning that it included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0002666; HP:0000107; HP:0001737 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Pheochromocytoma, Renal cyst, Pancreatic cysts)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 31087189

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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

PatientID: Unknown

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 5 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: paraganglioma, hemangioblastoma, lung metastases and spinal hemangioblastoma but the presenting patient is unclear.Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 18 years later but it is unclear if this pertained to all affected family members.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The P76del (c.227_229del) germline mutation of the VHL gene was found in a 25 yr old VHL patient with hemangioblastomas of the central nervous system and pancreatic cyst or tumor (index case 280). No family information is provided.

PatientID: 27

KindredID: 27

Case: Sex Unknown, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107; HP:0009711; HP:0001732 (Pheochromocytoma, Clear cell renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (3kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 3kb

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. This silent mutation, c.183C>G, was found in a 58-year-old VHL patient with hemangioblastomas of the central nervous system (index case 52).

GroupID: 39

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: 0 GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0010797; HP:0009713; HP:0001737 (Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Pancreatic cysts/single cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

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

GroupID: 27

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0009711; HP:0010797; HP:0009713; HP:0001737; HP:0030424 (Renal cell carcinoma, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Pancreatic cysts (1), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

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