43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. Peripheral blood samples were directly sequenced on an automatic sequencer (ABI 3100, Applied Biosystems, Foster City, CA) and real-time quantitative PCR (RQ-PCR) was used to detect partial or complete VHL gene deletions. Two of the 43 patients (patients 19 and 13) were found to have the missense mutation, c.500G>A in the VHL gene. Patient 19 had multiple hemangioblastomas of the central nervous system and spinal cord as well as bilateral renal cell carcinoma. Patient 13 had hemangioblastoma (either of CNS or spinal cord-not indicated), ovarian cysts, pancreatic cysts, and renal cell carcinoma. Both patients had no family history and were classified as A2 (sporadic patients with involvement of at least two distinct organs).

PatientID: VHL-16

KindredID: 16

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Family history of VHL. No further details provided.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

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

CaseHPOFreeText: Multiple CNS hemangioblastomas. Clinical classification: A1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114R (c.340G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

At age 9, a male caucasian patient was admitted with hypertension and tachicardia. His history included café-au-lait spots since birth, four months of night sweats and three weeks of fevers, bifrontal headaches and fatigue. An MRI scan showed a 3cm left adrenal mass and an MIBG showed increased activity in the left adrenal gland. One month later the patient underwent a successfull adrenalectomy. Four years post-surgery, the patient presented with bitemporal headaches, fatigue and low-grade fevers but both MRI and MIGB are inconclusive. One year later, symptoms worsened, MRI results were negative. At 18Y he later relapsed with another adrenal pheochromocytoma which was resected. DNA analysis showed a germline mutation Val84Leu in VHL. This mutation could correspond to either c.250G>C or c.250G>T. Neither of the parents carried mutations of the VHL gene. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: N/A (case)

KindredID: 1

Case: F, 30Y0M, South-Asian (Indian)

DiseaseAssertion: VHL

FamilyInfo: Not stated - although she was counselled through a planned conception, and she delivered a healthy child

CasePresentingHPOs: HP:0006748; HP:0001732; HP:0006880 (adrenal pheochromocytoma; pancreatic mass; cerebellar hemangioblastoma)

CaseHPOFreeText: Here is a case report describing a young woman presenting with hypertension, diagnosed to have VHL with right adrenal pheochromocytoma, and a pancreatic mass. Subsequent brain scan revealed a cerebellar hemangioblastoma. The patient underwent an adrenalectomy where her diagnosis was confirmed. Additionally, surgery for cebellar haemangioblastoma and distal pancreaticospleenectoy were done.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98S (c.293A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 219160 https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

A case report of a 30 year old young Indian female who presented with hypertension and was subsequently diagnosed to have VHL disease with a c.293A>C mutation in the VHL gene, causing the substitution of Tyr with Ser at amino acid 98. Patient presented with adrenal pheochromocytoma, pancreatic mass, and cerebellar hemangioblastoma. Family history is unavailable other than the delivery of a healthy child. ACMG: PP2, PP4

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 #86. The proband (patient 229) was a male who was diagnosed with CNS hemangioblastoma at 39Y, retinal angioma at 57Y, renal cell carcinoma at 57Y, and multiple pancreatic cysts/tumors at 57Y. His sister (patient 230) was diagnosed with CNS hemangioblastoma at 40Y. His first brother (brother 1, patient 231) was diagnosed with retinal angioma at 25Y and renal cell carcinoma at 54Y. His second brother (patient 232), who passed away before he could be genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 35Y. His nephew (son of second brother, patient 233) was diagnosed with a renal cell carcinoma at 30Y. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 175

KindredID: 69

Case: F, 35Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The male proband, patient 143, was diagnosed with renal cell carcinoma and multiple pancreatic cysts/tumors at age 33. His mother, who was not confirmed with the mutation, had a CNS hemangioblastoma at 30, retinal angioma at 54, and renal cell carcinoma at 50. His sister had a CNS hemangioblastoma at 28, and renal cell carcinoma/ multiple pancreatic cysts/tumors at 35. His niece, who was not confirmed with the mutation, had a CNS hemangioblastoma at age 12. His aunt had a CNS hemangioblastoma at 37, retinal angioma at 45, and renal cell carcinoma at 53. The son of his aunt was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband's sister presented with a CNS hemangioblastoma at age 28 and renal cell carcinoma and multiple pancreatic cysts/tumors at age 35.

CaseNotHPOs: HP:0002666; HP:0009711 (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.C162W (c.486C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

PatientID: 140

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 son was asymptomatic at the time of assessment.

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

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. One female patient, patient 112, was found with this germline mutation from family #40. Shee was diagnosed with a CNS hemangioblastoma at 34Y, renal cell carcinoma at 44Y, and multiple pancreatic cysts/tumors at 44Y. This kindred was likely also published in a later 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. One male patient was found with this germline mutation from family #45. He was diagnosed with CNS hemangioblastoma at 30Y. One male patient was found with this germline mutation from family #46. He was diagnosed with CNS hemangioblastoma at 30Y, RCC at 31Y, pheochromocytoma at 30Y, and multiple pancreatic lesions at 30Y. No other family information was published for these two patients. Both kindreds were also likely published in a paper by Wang et al., 2018 (PMID: 29330336). Kindred #46 was also previously published in Wang et al., 2014 (PMID: 24581539). Wang et al., 2018 reported 4 patients from 2 families (corresponding with kindred #45 and #46) who were genetically confirmed with this germline mutation. Wang et al., 2014 reported one patient who was genetically confirmed with this germline mutation likely corresponding with family #46.

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. Genotyping confirmation was performed by PCR-direct sequencing on peripheral blood samples. This mutation was confirmed in families #4, #5, and #5. Only the proband of family #4 (male, patient #7) was genetically confirmed with the mutation. He was diagnosed with renal cell carcinoma and multiple pancreatic cysts/tumors at age 33. Only the proband of family #5 was genetically confirmed with the mutation. He presented with a CNS hemangioblastoma at age 21 and multiple pancreatic cysts and tumors at age 30. His grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease. Family #6 is large: the proband (F, renal cell carcinoma at age 36 and pheochromocytoma at age 37) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13 (asymptomatic,) 14 (CNS hemangioblastoma at age 59,) 15 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19 (asymptomatic), 20 (asymptomatic), 21 (CNS hemangioblastoma and retinal angioma at 53,) and 22 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16 (CNS hemangioblastoma at 22) and 17 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51). This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 93

KindredID: 30

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 51.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.E94* (c.280G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

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

MultipleGeneVariants: N/A

37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. One family with 2 patients (Family ID7) was found with a germline missense mutation in the VHL gene (R167W; c.499C>T). Patient 1 was diagnosed at 4Y and had 3 retinal hemangioblastomas at 8Y and 16Y. Patient 1 was 40 by the end of the study. Patient 2 was diagnosed at age 13Y and had no manifestations by the end of the study when they were 36Y.

PatientID: I

KindredID: 18

Case: Sex Unknown, 48Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0000112 (Pancreatic cysts, Nephropathy)

CaseHPOFreeText: Diagnosed with VHL at age 14Y. Presented with 3 pancreatic cysts (14Y) and kidney disease (16Y). Age at the end of study: 48Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q203Tfs*53 (c.606dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 935385, https://www.ncbi.nlm.nih.gov/clinvar/variation/935385/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: Q203TfsX53 (c.606dupA)

MultipleGeneVariants: N/A

37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. Parts of the Danish cohort have been previously assesed in the following papers PMID: 19863552, 25834951, 27966541, 27539272. Peripheral blood samples were isolated and sequenced coding exons and exon-intron boundaries using MLPA (Multiplex Ligation-dependent Probe Amplification). One family with one patient (Family ID14) was found with a germline mutation in the VHL gene (R161*; c.481C>T). The patient was diagnosed at 10Y and had 2 epididymal cystadnomas at 10Y. The patient was 46 by the end of the study.

A case report revealed a 47Y female patient with two synchronous kidney tumors on the right side that were clear cell renal cell carcinoma and cystic renal cell carcinoma, and a clear cell pancreatic neuroendocrine tumor. She also presented with multiple pancreatic and renal cysts. Genetic analysis confirmed a c.257C>G (p.Pro86Arg) mutation in the VHL gene. The patient had a positive family history with their mother and brother having VHL disease, but genotypic and phenotypic information for family members was not available.

PatientID: None

KindredID: 39

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 39

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown or unstated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Unknown evidence for pheochromocytoma (neither yes nor no was stated) in this family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: S65W (c.407C>G)

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

In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma (PC). Deletions, nonsense, and frameshift mutations were more frequently found in families without PC. Large deletions and mutations predicted to cause truncated protein were associated with lower risk of PC. The mutation R177* (c.499C>T) was referred to in the paper by c.712C>T due to a difference in transcript sequence. This missense mutation was found in one of the VHL families (family ID 153).

PatientID: V-4

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: V-11

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: V-30

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

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 was 1 patient reported with the c.262T>A (p.W88R) mutation. This member presented with retinal hemangiomas. No family information was provided.

GroupID: 41

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 30b

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: N/A

CaseHPOFreeText: This was 1 of 5 patients discussed with this mutation. The individual did NOT have retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107H (c.320G>A)

MultipleGeneVariants: N/A

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. There was 1 patient reported with the c.386T>C (p.L129P) mutation. This member presented with retinal hemangiomas. 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 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. Out of the 3 patients with a p.Q164* (c.490C>T) mutation, 67% (2/3) of individuals had RH while 33% (1/3) did not. No family information was provided.

A case report of a 31 year old female patient diagnosed with VHL disease revealed a c.481C>T mutation in the VHL gene, leading to the subsequent protein change Arg161*. Tissue resection was analyzed through DNA amplification. There was no family history of illness. Over an 8 year follow-up period the 31Y old patient presented with bilateral RCC, bilateral renal cysts, cardiomegaly, multiple brain hemangioblastomas, pancreatic neuroendocrine carcinoma, pancreatic cysts, kidney cysts, and ovarian cysts.

Medical records of 45 Italian patients with pheochromocytoma/paraganglioma referred to the hypertension centers of the University of Brescia and the University of Turin were reviewed. Germline DNA was extracted through peripheral blood, and PCR products were purified. Only familial and sporadic cases of isolated PHEO/PGL were considered. Patient number 10 was found with a germline VHL mutation (p.P81L) and left para-adrenal paraganglioma, apparently sporadic. This patient was reported to have a negative family history. ACMG: 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. This missense mutation was found in a VHL type 2B family of 7 individuals (Family ID 4414), using PCR and SSCP sequencing. The mutation of c.357C>G was referred to in the paper by c.570C>G due to a difference in transcript sequence. Two of seven individuals were identified with retinal hemangioblastomas, 3 with CNS hemangioblastomas, one with renal cell carcinoma, and one with pheochromocytomas. 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).

PatientID: None

KindredID: 3618

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.C233W (c.699C>G)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

GroupID: 3682b

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. Paper gives 2 families with the ID 3682 - the other family (given here as 3682a) was mentioned with 1 individual. Unclear if these are the same family.

GroupPresentingHPOs: HP:0010797 (hemangioblastoma)

GroupHPOFreeText: both (2/2) members had hemangioblastomas

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.F76I (c.226T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F147I (c.439T>A)

ClinVarID: 820994 https://www.ncbi.nlm.nih.gov/clinvar/variation/820994/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F76I (c.226T>A)

MultipleGeneVariants: N/A

GroupID: 2547

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

GroupHPOFreeText: 3/5 members had a retinal angioma (hemangioma), 4 had CNS hemangioblastoma, and 2 had pheochromocytoma

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 2 2547NCI);

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.G164D (c.491G>A )

ClinVarID: 496054 https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

GroupID: 4405

DiseaseAssertion: assumed VHL

GroupSize: 41

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 41 family members recorded with this mutation.

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

GroupHPOFreeText: 29/41 members had retinal angioma (hemangioma), 10 had CNS hemangioblastoma, 15 had RCC and 28 had pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 2 4405NCI)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

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 3 VHL type 1 family members (family ID 3738), using PCR and SSCP sequencing. The mutation of c.334T>C was referred to in the paper by c.547T>C due to a difference in transcript sequence. All had pheochromocytomas and one with retinal hemangioblastomas.

PatientID: 6

KindredID: 2

Case: M, 52Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: Another member of this family (Gen 1) presented with the same mutation and bilateral pheochromocytoma.

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

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

CaseHPOFreeText: Bilateral pheochromocytoma. Cause of death: neural hemangioblastomas.

CaseNotHPOs: HP:0001737; HP:0009711; HP:0002668; HP:0030405 (Pancreatic cysts, Retinal capillary hemangioma, Paraganglioma, Pancreatic endocrine tumor)

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

Medical records of 31 Asian Indian genetically proven VHL patients with pheochromocytoma/paraganglioma were studied. A 30 year old male (Patient 23) presented with unilateral pheochromocytoma (30Y). Genetic testing (PCR and Sanger sequencing) confirmed a missense mutation at c.509T>C of the VHL gene. He has a negative family history.

PatientID: 31

KindredID: 31

Case: M, 21Y0M, Asian Indian

DiseaseAssertion: pheochromocytoma

FamilyInfo: None - apparently sporadic

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: patient had unilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q (c.533T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L178Q (c.533T>A)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 15

Case: M, 12Y0M, Asian Indian

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0000107; HP:0001737 (pheochromocytoma; paraganglioma; renal cyst; pancreatic cysts)

CaseHPOFreeText: unilateral pheochromocytoma with sympathetic paraganglioma. Renal and pancreatic cysts

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98S (c.293A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 219160 https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y98S (c.293A>C)

MultipleGeneVariants: N/A

GroupID: None

KindredID: 16

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed /Latino

GroupAgeRange: N/A

GroupInfo: Four members of a South American family expressed this 462-95T>A mutation.

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

GroupHPOFreeText:Two family members had hemangioblastoma of the central nervous system. Three had pheochromocytoma.

GroupNotHPOs: HP:0002894, HP:0009711, HP:0005584 (neoplasm of the pancreas, retinal capillary hemangioma, renal cell carcinoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-94T>A

LegacyVariant: IVS2-95T>A

CaseProblemVariantFreeText: N/A

ClinVarID: 1201249 https://www.ncbi.nlm.nih.gov/clinvar/variation/1201249/?oq=1201249&m=NM_000551.4(VHL):c.464-94T%3EA

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: intron_variant

CivicName: R167Q(c.500G>A) and c.464-94T>A

MultipleGeneVariants: Germline, VHL, c.500G>A (Arg167Glu)

Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 VHL family members (VHL family 3). One had hemangioblastomas of the central nervous system and one had retinal angiomas. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

Germline mutations were found in 20 Brazilian, VHL probands and their families. The S80R (c.238A>C) germline missense mutation was found in a VHL type 1 family of 10 affected individuals (VHL family 2). Seven had hemangioblastomas of the central nervous system, 3 had retinal angiomas, and 3 had renal carcinoma. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

Direct sequencing and multiplex ligation dependent probe amplification were performed on thirteen unrelated subjects with VHL mutations. The clinical manifestations and family histories of the subjects were evaluated. A 14 year old Korean male patient presented with central nervous system hemangioblastoma, retinal hemangioblastoma, multiple pancreatic lesions, and bilateral renal cysts. Genetic testing confirmed a non-familial missense mutation at c.233A > G of the VHL gene. The patient had no family history of VHL.

PatientID: VHL_16 (tumor ID)

KindredID: 16

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at an unknown age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175C (c.524A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36905, https://www.ncbi.nlm.nih.gov/clinvar/variation/36905/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y175C (c.524A>G)

MultipleGeneVariants: N/A

PatientID: VHL_8 (tumour ID)

KindredID: 8

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal Pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at age 24.

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

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 13

Case: age, sex, ethnicity unknown

DiseaseAssertion: Unknown

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Described as a positive control but not stated anything further

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely previously published - not clear where the controls came from/ how they were used.

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: age, sex, ethnicity unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

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

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 C162R (c.484T>C) germline mutation of the VHL gene was found in a VHL type 1 family of 6 presenting with CNS hemangioblastoma (1/6), retinal angioma (2/6), renal cell carcinoma (3/6) and pancreatic tumor or cyst (unspecified) (1/6) (family ID 4). This family was previously reported in PMID 8634692.

PatientID: None

KindredID: 8

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

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

LegacyVariant: c.476G>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

PatientID: 8 (Cousin)

KindredID: 17

Case: F, 4Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 6 members of this family tested positive for the c.496_506del germline variant of the VHL gene. ID 4 presented with CNS hemangioblastoma, retinal angioma and renal and pancreatic abnormalities. ID 1 and 25 were asymptomatic.ID 22 presented with CNS hemangioblastoma. ID 5 presented with retinal angioma. 2 members were assumed to have the variant but were not genetically confirmed (ID 20 and ID 11). ID 11 and 20 presented with CNS hemangioblastoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666; HP:0010797; HP:0000077; HP:0001732; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Abnormality of the kidney, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.V166Sfs*4 (c.496_506del)

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/AVariantEvidence: It is unclear from the publication if this variant is reported according to legacy (AF010238.1) or NM_000551.3 reference sequence. Clinical notes from the case confirm the reference sequence to be NM_000551.3.

MutationType: deletion; minus_2_frameshift_variant

CivicName: V166SFS*4 (c.496_506del)

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 12

Case: M, 57Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient had a father that was assumed to have the c.406T>C germline mutation of the VHL gene but was not confirmed genetically. His father presented with renal cell carcinoma and died at 47Y.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000077; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Abnormality of the kidney, Abnormality of the pancreas)

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (37Y), retinal angioma (27Y) and renal and pancreatic cyst or tumor (unspecified) (28Y).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.406T>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reference sequence is unclear in the current paper. After consulting the SickKids patient database, and finding the protein change to be recorded as: p.Ser65Pro, it was concluded that the current paper reported the cDNA change according to the legacy reference sequence (AF010238.1) and was mapped to c.193T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

PatientID: 21 (Aunt)

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. ID 35 was asymptomatic. IDs 1 (proband), 28, 2, 6, 17 and 19 all presented with pheochromocytoma. ID 5 presented with CNS hemangioblastoma, retinal angioma and renal cyst OR tumor (not specified).

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

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 39 and retinal angioma at age 41.

CaseNotHPOs: HP:0005584; HP:0001732; HP:0000077; HP:0010797 (Renal cell carcinoma, Abnormality of the pancreas, Abnormality of the kidney, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.S65A (c.193T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223160, https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 7

Case: M, 12Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family were found to harbor the c.319C>G germline variant of the VHL gene. ID 11 presented with renal and pancreatic abnormalities, pheochromocytoma and other undefined phenotypes. ID 24 presented with renal abnormalities, and pheochromocytoma, and died at age 62. ID 2 presented with pancreatic abnormalities. ID 10 presented with CNS hemangioblastoma, pancreatic abnormalities and pheochromocytoma. ID 4 presented with pheochromocytoma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented pheochromocytoma (4Y).

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0010797; HP:0000077 (Retinal capillary hemangioma, Renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France). No variants were found in 96 control cases. This splice site mutation, c.340+1G>A (stated as IVS1+1G→A in the paper), was found in a VHL type 2B patient (no. V283). Type 2B VHL families are described as having pheochromocytoma and presence of renal and pancreatic manifestations. No family information was provided.

GroupID: V8

DiseaseAssertion: VHL

GroupSize: 14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: Patients are grouped by family.

FamilyInfo: 14/27 members of this family that underwent genetic testing had the same mutation.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Diagnosed with VHL Type 1.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T105P (c.313A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496055, https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: T105P (c.313A>C)

MultipleGeneVariants: N/A

PatientID: V233

KindredID: V233

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: One unaffected family members were tested and found to be negative. No other family history was available.

CohortInfo: 92 unrelated patients with VHL disease.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N131K(c.393C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 420074 https://www.ncbi.nlm.nih.gov/clinvar/variation/420074/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:N131K(c.393C>A)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France). No variants were found in 96 control cases. This stop-gain mutation, c.525C>G, was found in a VHL type 1 patient (patient no. V63). No patient information was provided and no additional family members were screened.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The Y156C (c.467A>G) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V265). One unaffected family member was negative for this mutation.

A retrospective study reviewed cases of 23 patients with advanced and complicated VHL eye disease who underwent pars plana vitrectomy in the years 1999 to 2012 that were a part of 223 VHL patients consulted at the International Hereditary Cancer Center and Polish VHL Registry. Genetic molecular analysis was performed in 22/23 patients through PCR and MLPA, and 24 eyes from 23 patients were studied. A germline c.481C>T transition was would in 3 individuals, and results in a p.Arg161* protein change and premature stop codon. A 35 year old (Patient 3) had a previous history of HbCNS. Patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery. A 35 year old patient (Patient 7) had a previous history of HbCNS and RCC. The patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery. An 18 year old (Patient 9) had a previous history of HbCNS, ELST, and RCC. Patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery. Since patients were listed 'by eye' it is impossible to determine how many patients listed above actually represent unique patients.

PatientID: 21

KindredID: 21

Case: 23Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; 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: c.464-1G>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: Stated in paper as “IVS2-1G>T”

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: None (proband 15)

KindredID: 15

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Father had died before diagnosis therefore no DNA sample available; He presented with CNS hemangioblastomas at the age of 42.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715; HP:0030393 (hemangioblastoma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis, endolymphatic sac tumor)

CaseHPOFreeText: Patient presented with hemangioblastoma at age 29, renal cell carcinoma at age 29, pancreatic cysts at age 36, endolymphatic sac tumor at age 33, papillary cystadenoma of the epididymis at age 29.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

During the period from 2009 to 2012, 39 families with VHL disease were diagnosed with hereditary VHL disease at Peking University First Hospital Department of Urology were described as part of a broader study examining telomere length and anticipation. In these families, 19 families had two or more than two patients in two or more than two generations, including one family with obscure onset age. Therefore, a total of 57 patients with VHL disease from 18 families were enrolled in this study. Using peripheral blood and southern blotting, DNA sequencing was completed on the following patients. Family 4 involved three affected members, however only two of which were known to have a c.269A>T change leading to a p.Asn90Ile protein change. The male proband presented with hemangioblastoma at 22 and retinal capillary hemangioma at 32. His mother presented with renal cell carcinoma at 63. The proband’s brother died before diagnosis; thus no DNA sample available, however he was affected with hemangioblastoma at age 19Y. Of family 9, the male proband presented with hemangioblastoma at 28, renal cell carcinoma at 38, and pancreatic cysts at 38. His mother, aunt and cousin all died before diagnosis; thus no DNA sample available. The mother was last observed at 33Y with CNS hemangioblastoma; the aunt at 32Y with hemangioblastoma, and the cousin at 30Y with hemangioblastoma. ACMG Evidence Code: 'PP4' because the patients' phenotypes and family histories are highly specific for VHL disease.

PatientID: None (Daughter)

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's mother had pancreatic islet cell adenoma, renal cell carcinoma, extraadrenal pheochromocytoma, and spinal cord lesion. Her brother had the same VHL gene mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: I-1

KindredID: 1

Case: F, 54Y0M (deceased), Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. I-1 had 16 children, with many grand/great/great grand children. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0002090 (Pneumonia)

CaseHPOFreeText: Patient was thought to have had olivopontocerebellar atrophy (OPCA) for much of her adult life. Her OPCA is now explained by the detection in her kindred of spinocerebellar ataxia type 2 (SCA2). Her VHL was diagnosed at the age of 48 years. She died of pneumonia aged 54 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: SCA2 (an abnormal increase in CAG repeats in one allele of her ataxin-2 gene. This abnormal trinucleotide expansion is consistent with the diagnosis of spinocerebellar ataxia type 2)

PatientID: sister

KindredID: C

Case: F, 34Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Family history is positive. Patient’s sister, and son all had the splice mutation, two with CNS hemangioblastomas and one with pheochromocytoma

CasePresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, papillary cystadenoma of the epididymis)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 34Y, and adnexal papillary cystadenoma of probable mesonephric origin diagnosed at 35Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

PatientID: proband

KindredID: D

Case: F, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Family history is said to be positive, however no other members were given. The patient’s son was asymptomatic and negative for the mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 34Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Q145* (c.646C>T)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: proband

KindredID: C

Case: F, 29Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Family history is positive. Patient’s sister, and nephew all had the splice mutation, and sister and nephew had CNS hemangioblastomas and adnexal papillary cystadenoma of probable mesonephric origin, and pheochromocytoma phenotypes. Her daughter was asymptomatic and did appear to not carry the mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 29Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 6

Case: 29Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Positive family history

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

CaseHPOFreeText: Aged 22Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS and retinal hemangioblastoma was diagnosed at 22, pancreatic cysts and renal cysts were diagnosed at 29Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: absence of pheochromocytoma/paraganglioma (pheo/pgl) after 14 years of follow-up.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation (c.245G>T) was detected by direct sequencing and MLPA in a VHL kindred with pheochromocytoma (case no. 393). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation (c.266T>C) was detected by direct sequencing and MLPA in 2 VHL kindreds. It was found in a kindred with hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic and renal cysts (case no. 23530). 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 patient's phenotypes or family history are highly specific for a disease with single genetic etiology.

Of 46 cases of RCC in patients younger than 25 years, one patient (case 45) was found to harbour a germline VHL splicing mutation G>C at position 340+5, stated in the paper as c.553+5 due to a difference in transcript sequence. Genomic DNA was extracted using DNeasy Blood and Tissue Kit, from neoplastic and non-neoplastic tissue samples and was analyzed for polymerase chain reaction-based loss of heterozygosity (LOH) where results were viewed by silver nitrate staining. This patient presented with a papillary RCC (stage/diameter: pT1N0M0) on her right kidney at age 16. She presented no evidence of disease at her 36 month follow-up after undergoing a radical nephrectomy. She had a known family history for VHL disease and her mother has cerebellar hemangioblastoma. Genetic data on the mother was not described. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 6

KindredID: 1

Case: Sex Unknown, 60Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

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

CaseHPOFreeText: 49Y at first pheochromocytoma and ocular angioma (retinal capillary hemangioma). Total of 3 ocular angiomas and 1 pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

188 individuals presenting with a single hemangioblastoma, no family history of VHL disease, and no evidence of retinal or abdonimal manigestations of the disease at the time of diagnosis, were were investigated for mutations in the VHL gene. Patient B5 presented with a cerebellar hemangioblastoma at age 39. Genetic testing via direct sequencing on a DNA blood sample found a c.598C>T (p.Arg200Trp) mutation in their VHL gene (noted as c.811C>T in the paper due to their use of an older VHL transcript used for mapping).Two first-degree relatives (FDRs) tested positive for the mutation: a 28 year old FDR and a 38 year old FDR, neither of whom showed any features of VHL disease. Patient B4 presented with a cerebellar hemangioblastoma at age 36. Genetic testing via direct sequencing on a DNA blood sample also found a c.598C>T (p.Arg200Trp) mutation in their VHL gene (noted as c.811C>T in the paper due to their use of an older VHL transcript used for mapping). No family germline testing was performed, and no features of VHL disease were noted in their family history.

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.R167Q (c.500G>A) mutation, 24 members total from 10 families were described, and phenotypic information was given for this group. With ages of onset ranging from 14-53Y, hemangioblastomas were observed in 15/24 members, retinal capillary hemangioma in 4, renal cell carcinoma in 10, pancreatic cysts in 5, and pheochromocytoma in 9 members. This cohort has been previously published in PMID 24581539 (as family #11); 29330336 (as 7 families of 18 people); 28388566 (family #78, 79, 80, 81, 82, 83).

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.W117G (c.349T>G) mutation, 11 members total from 2 families were described, and phenotypic information was given for this group. With ages ranging from 12-61Y, hemangioblastomas were observed in 8/11 members, retinal capillary hemangioma in 5, renal cell carcinoma in 6, pancreatic cysts in 8, pheochromocytoma in 1 member and and in a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) 1 member. See more information as this cohort has been previously published in 24581539 (as family 6 of 10 members); 29330336; and 28388566.

GroupID: 14

DiseaseAssertion: assumed VHL

GroupSize: 11

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 28.8Y +/- 19.6Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 11 members total were described, and phenotypic information was given for this group.

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

GroupHPOFreeText: 6 of the 11 members presented with CNS hemangioblastoma (with a mean age of 33.0Y), renal cell carcinoma in 4 members (at the mean age of 42.3Y), pancreatic cysts in 4 members (also at the mean age of 42.3Y), and a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) in 1 member at the age of onset of 10Y

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

GroupNotHPOFreeText: No patients presented with retinal capillary hemangioma or pheochromocytoma

GroupPreviousTesting: N/A

PreviouslyPublished: see more information in 29330336 (2 families of 11 people total), and 28388566 (as family #52 (9 members), and #53 (2 members)).

SupplementalData: N/A

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: None

KindredID: 3618

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0030405 (Pheochromocytoma, Hemangioblastoma, Pancreatic endocrine tumor)

CaseHPOFreeText: Diagnosed with CNS hemangioblastoma, pheochromocytoma, cysts and VHL Type 2B. Localized pancreatic neuroendocrine tumor is also associated with this family but the number of family members affected is not specified.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040; 7728151

SupplementalData: N/A

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

LegacyVariant: c.699C>G

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 699, C to G (Cys to Trp), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.486C>G, p.Cys162Trp (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

GroupID: 4409

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Each group represents a family.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584; HP:0030405 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma, Pancreatic endocrine tumor)

GroupHPOFreeText: 1/2 members with pheochromocytoma, 1/2 members with CNS hemangioblastoma, 2/2 members with retinal angioma, 2/2 members with RCC and 2/2 members with cysts. Diagnosed as a VHL Type 2B family. Metastatic pancreatic neuroendocrine tumor is also associated with this family but the number of family members affected is not specified.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 10458336; 7728151

SupplementalData: N/A

Variant: p.G114R (c.340G>C)

LegacyVariant: c.553G>C

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 553, G to C (Gly to Arg), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.340G>C, p.Gly114Arg (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: F, 33Y0M, Ethnicity Unknown

DiseaseAssertion: endolymphatic sac tumor

FamilyInfo: Her mother and elder sister had history of resection of cerebellar hemangioblastomas, although no genetic testing was done for them.

CasePresentingHPOs: HP:0030393 (endolymphatic sac tumor)

CaseHPOFreeText: Woman had progressive hearing disturbance, vertigo, and headache since 32Y. MRI revealed a 4.5 × 3.8 × 3.5-cm mass was detected in the right cerebellopontine angle, destroying the cerebellum. CT with a bone window mode demonstrated extensive destruction of the petrous bone and middle ear structures (endolymphatic sac tumor). The patient underwent craniotomy for a complete removal of the tumor. To date of publication, the patient remains well, with no evidence of recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

LegacyVariant: 553 + 1G→A, designated as IVS1 + 1G→A mutation

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: No LOH was found in this sample

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 23

KindredID: 23

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

CasePresentingHPOs: HP:0002666, HP:0002864, HP:0009711, HP:0001737 (pheochromocytoma, paraganglioma of head and neck, retinal capillary hemangioma, pancreatic cysts)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9880225

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: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: I (mother)

KindredID: F12

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 4 members of this family (I.mother, II.daughter, II.son, III.granddaughter) presented with pheochromocytoma and were found to have the P138= (c.414A>G) germline variant of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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; synonymous_variant

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

A case report describes a 35 years old women presenting with osteoporosis. Her past medical history revealed retinal angioma at 16 years, cerebellar hemangioblastoma at 21 years, spinal hemangioblastoma at 28 years, pheochromocytoma at 32 years, and amenorrhea (started menstruating at age 12 and stopped at 16). She had a germline p.Arg167Gln mutation in the VHL gene. She had a negative family history for VHL disease and osteoporosis, but gentoype of family members was not described.

GroupID: 20B

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.L158V (c.472C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 567944 https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

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. 2 patients were found to have the above mutation (c.340G>A). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was 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: 18B

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

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 patients with the given mutation were grouped as group 18(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-2A>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-2A>G)

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. 13 patients were found to have the above mutation (c.482G>A). 5 were VHL patients with ICTs (pancreatic neuroendocrine tumors) taken from the VHL-registry. The other 8 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.

A retrospective analysis of pheochromocytoma tissue samples from the Department of Pathology of the Erasmus MC (Rotterdam) revealed an 18Y female patient (ID #F119) with a confirmed germline mutation in the VHL gene, p.Arg64Pro. The patient had pheochromocytoma but other phenotypes were not described. Family history was not described. Pheochromocytoma is highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).

PatientID: 1

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: renal cell carcinoma

FamilyInfo: None

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.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: patient has a germline deletion of VHL gene demonstrated by loss of one open-reading frame signal detected by g7 cDNA probe. Renal cell carcinoma sample from this patient shows a missense somatic mutation I151S(c.452T>G) in the second copy of VHL gene.

MutationType: missense_variant; transversion

CivicName: Deletion AND I151S (c.452T>G)

MultipleGeneVariants: Germline, VHL, deletion

PatientID: IV-6 (Proband)

KindredID: 2

Case: F, 23Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 12

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient has no family history of VHL disease. They were identified as sporadic with their parents being excluded from having a germline mutation.

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001737; HP:003042 (hemangioblastoma, renal cyst, pancreatic cysts, epididymal cyst)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152P (c.454A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 928821 https://www.ncbi.nlm.nih.gov/clinvar/variation/928821/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: T152P (c.454A>C)

MultipleGeneVariants: N/A

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summariezed the phenotypes of the families together. Family 2 was found with p.Glu70* mutation in the VHL gene: 1/2 members had CNS hemangioblastoma. 1/2 had retinal angioma, and 1/2 members had a pancreatic lesion. ACMG PP4

GroupID/ KindredID: 3

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 6 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0005584; HP:0001732 (hemangioblastoma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: 5 members had CNS hemangioblastomas, 1 member had RCC, and 1 had pancreatic cysts or tumors (an abnormality of the pancreas)

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

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q73* (c.217C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Q73* (c.430C>T)

ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: II-2

GroupID/ KindredID: 6

Case: Age unknown (deceased), M, Chinese

DiseaseAssertion: hemangioblastoma

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

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: No VHL gene test was conducted but due to substantial family pedigree history, can assumed with confidence this mutation

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

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 9 and 10 were found with p.Pro86Leu mutation in the VHL gene. Family 9: the mutation was detected in a 53 years old woman (proband) with asynchronous bilateral renal clear cell carcinomas, multiple renal cysts and pancreatic cysts, an asympomatic member and with (initially) no positive family history. Subsequently, genetic analysis and clinical evaluations showed that the same mutation was also detected in her niece who had no detectable VHL lesions and in her young brother who had pancreatic cysts. Family 10: 1/4 members had CNS hemangioblastoma, 1/4 had retinal angioma, 2/4 had RCC, and 1/4 had a pancreatic lesion. ACMG PP4

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summariezed the phenotypes of the families together. Family 14 was found with p.Ser111Asn mutation in the VHL gene: 4/5 members had CNS hemangioblastoma, 1/5 had retinal angioma, 3/5 had RCC, and 1/5 had a pancreatic lesion. ACMG PP4

GroupID/ KindredID: 18

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 2 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0005584; HP:0001732 (hemangioblastoma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: both (2) members had CNS hemangioblastomas, 1 had RCC, 1 had a pancreatic abnormality

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

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.C162Y (c.698G>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

PatientID: None

KindredID: 1

Case: M, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was unremarkable and proband has no children.

CasePresentingHPOs: HP:0006770; HP:0006880; HP:0001737; HP:0001289; HP:0005584 (Clear cell renal cell carcinoma, Cerebellar hemangioblastoma, Pancreatic cysts, Confusion, Renal cell carcinoma)

CaseHPOFreeText: Presented at age 39 with bilateral renal tumors (2 right side, 3 left side). Pathological evaluation revealed clear cell type renal cell carcinoma (fig. 1, B). After 2 years multiple pancreatic cysts were noted. Two years later 6 bilateral renal cell carcinoma lesions developed. Five years later at age 48 years mental confusion developed and brain MRI showed a cerebellar lesion; histological evaluation revealed cerebellar hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.699C>G

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A