A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. Patient ID 66 was found with this germline mutation (c.408delT) and no manifestations. Authors were contacted and other patients with this mutation (Patients 46, 50, 71, and 72) were reported previously in Aronoff et al, 2018 (PMID: 29437867) as family 5. Patients' age and sex were not reported. ACMG PP4

PatientID: None

KindredID: 8

Case: M, 15Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma; paraganglioma; retinal capillary hemangioma)

CaseHPOFreeText: Benign sympathetic Paraganglioma at age 12Y0M and unilateral pheochromocytoma at age 15Y0M; as well as retinal angioma (age unclear)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

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: Y98S (c.293A>C)

MultipleGeneVariants: N/A

PatientID: 52

KindredID: 2

Case: Sex Unknown, 23Y0M, Norwegian

DiseaseAssertion: pheochromocytoma

FamilyInfo: Yes, a family history of neuroendocrine tumor (NET). They have another family member with the same mutation and pheochromocytoma.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Preoperatively presented with hypertension; surgery at 23Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: NF1, RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119S (c.356T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753715 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.356T%3EC

gnomAD: N/A

VariantEvidence: This mutation was found in DNA from the adjacent normal tissue, and this finding was found to be reproducible. The same VHL variant was later on observed in a family member with PHEO.

MutationType: missense_variant;transition

CivicName: F119S (c.356T>C)

MultipleGeneVariants: N/A

PatientID: 53

KindredID: 53

Case: M, 36Y0M, Korean

DiseaseAssertion: VHL

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

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

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

CaseHPOFreeText: CNS hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 44

KindredID: 44

Case: M, 30Y0M, Korean

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0002666; HP:0010797 (Pheochromocytoma, Hemangioblastoma)

CaseHPOFreeText: Multiple or bilateral pheochromocytoma. CNS hemangioblastoma. Diagnosed with VHL Type 2A.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16142346; “Kim, J. W., Choi, S. J., Kim, Y. K., Ahn, S. M., Song, K. E., Jung, S. H. et al. A case report of von Hippel–Lindau disease manifested in a monozygous twin. J. Korean Soc. Endocrinol. 20, 395–400 (2005)” (Reference 15 in current publication).

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

GroupID: 33

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:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0030424 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (3), Retinal capillary hemangioma (3), Hemangioblastoma/brain/cerebellum (4), Spinal hemangioblastoma (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

GroupID: 17

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:0009713; HP:0030393; HP:0001737 (Renal cell carcinoma, Retinal capillary hemangioma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Retinal capillary hemangioma (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Pancreatic cysts (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 2 Deletion (c.341-?-463+?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 2 Deletion

MultipleGeneVariants: N/A

GroupID: 21

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:0002666; HP:0009711; HP:0010797; HP:0009713; HP:0001737; HP:0030424 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Pheochromocytoma (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 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: VHL_6 (tumor ID)

KindredID: 6

Case: F, 31Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 31Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164R (c.491A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2238, https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q164R (c.491A>G)

MultipleGeneVariants: N/A

PatientID: VHL_11 (tumour ID)

KindredID: 11

Case: F, 47Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal Pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at age 47.

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

Two groups were analyzed for germline VHL mutation where Group 1 (84 individuals) presented with only one hemangioblastoma and no other clinical VHL features and those in Group 2 (4 individuals) presented with multiple hemangioblastomas and no other VHL clinical features. Peripheral blood analysis was conducted of all exons and flanking regions (90 nucleotides upstream and 45 downstream) of the VHL gene (numbered using Genbank accession number L15409). Southern blot, PCR and SSCP were performed. The c.241C>T (P81S) mutation - referred to in the paper by c.454C>T due to a difference in transcript sequence - was found in 1 patient (D24) from Group 1. She was 47 years of age and had four clinically unaffected first and second degree relatives (father (77Y0M), son (17Y0M), step-sister (43Y0M) and paternal aunt (64Y0M)) carrying this mutation. She presented with a solitary cerebellar hemangioblastoma. All other members were asymptomatic.

A cohort of 64 pheochromocytoma and paragangliomas were screened for a BRAF mutation using direct Sanger sequencing and QRT-PCR. Genomic DNA was extracted from fresh or frozen peripheral blood. Germline mutations of VHL, SDHB, SDHD, and RET genes were also observed. The VHL mutation c.602T>C (p.L201P) was reported in patient #3, a 12Y female with bilateral pheochromocytoma. No family history was reported here.

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

GenotypingMethod: Sanger sequencing

SamplingMethod: genomic DNA extracted from fresh or frozen peripheral blood

PatientID: Unknown

KindredID: 4

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 3 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: hemangioblastoma, parathyroid nodule, and esophageal carcinoma 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; HP:0002668 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 25 years later but it is unclear if this pertained to all affected family members. VHL type 2C.

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

PatientID: III:8

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Look to proband (III:3) for extensive family info.

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

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 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

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 1 patient (Family ID11) was found with a germline missense mutation in the VHL gene (Y98C; c.293A>G). The patient was diagnosed at 0Y and had 1 retinal hemangioblastoma at 12Y and 1 CNS hemangioblastoma at 6Y. Patient 1 was 13 by the end of the study.

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 3 patients (Family ID 1) were found to harbor the germline missense mutation in the VHL gene (c.500G>A; p.Arg167Gln). Patient 1 was diagnosed at 2Y old and had no manifestations. Patient 2 was diagnosed at 8Y and had retinal hemangioblastoma (8Y), pheochromocytoma (8Y), and kidney disease (8Y). Patient 3 was diagnosed at 9Y and had 3 retinal hemangioblastomas at 8Y and 16Y.

PatientID: II

KindredID: 2

Case: Sex Unknown, 5Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: One other family member presented with his VHL mutation and was asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 4Y. Age at the end of study: 5Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130I (c.388G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753916, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.388G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V130I (c.388G>A)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 8

Case: Sex Unknown, 35Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Diagnosed with VHL at age 15Y. Presented with 6 CNS hemangioblastomas (15Y) and 2 retinal hemangioblastomas (15Y). Age at the end of study: 15Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L118P (c.353T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428807, https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L118P (c.353T>C)

MultipleGeneVariants: Germline, VHL, c.319C>T (p.R107C)

This study investigated the effectiveness of whole exome sequencing (WES) and an in-house hybridization based gene panel (ENDOGENE Panel v2.0) at detecting mutations in pheochromocytoma/paraganglioma (PPGL) related genes. The ENDOGENE panel included EGLN1, EPAS1, FH, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, VHL, GOT2, MDH2 and SLC25A11. WES and the ENDOGENE panel were tested on 37 samples with known variants. After optimization of the bioinformatic pipeline, 61 additional samples were tested prospectively. VHL mutations were identified in 3 patients and all were confirmed by Sanger sequencing. Patient 48 was found to have an frameshift N193Mfs*9(c.576delA) deletion and diagnosed with adrenal pheochromocytoma which was said to be hormonally active. Genetic screening was performed in his parents and the same variant was detected in her clinically healthy mother (45 years old). Her screening for VHL-associated manifestation showed no VHL-related manifestations.

PatientID: 14

KindredID: 7

Case: Sex Unknown, 29Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: The patient developed PPGL at 29Y of age, and a PNET at 29Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

Of 31 Brazilian patients, two were found to harbour the c.371C>T (p.Thr124Ile) mutation of the VHL gene. Genomic DNA was extracted and all VHL coding regions were analyzed by Sanger sequencing. MLPA was performed to investigate large deletions using SALSA® MLPA® P016 VHL probe mix. Data analysis was performed with Genescan 3.7. These individuals were two males of the same family although their relation is not specified. Individual 26 presented with pheochromocytoma at age 13Y and pancreatic endocrine tumor at 47Y, along with renal cyst and retinal hemangioblastoma. Individual 27 presented with pheochromocytoma at 10Y with recurrence 48Y later.

PatientID: 6

KindredID: 4

Case: Sex Unknown, 44Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other family members were found to have the same mutation (Patient 7,8,9,10).

CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405, HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient was diagnosed with pancreatic endocrine tumor at age 44 and diagnosed with pheochromocytoma and paraganglioma at age 18.

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

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

GroupID: 21

Case: Age unknown, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

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

CasePresentingHPOs: Unknown

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0005584; HP:0002666; HP:0006880 (retinal capillary hemangioma; renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.T124Mfs*33 (c.371_377delCACACGA)

LegacyVariant: p.T124Mfs*33 (c.369_375delGACACAC)

CaseProblemVariantFreeText: written in paper as:c.369_375del, automaps to NM_000551.3:c.371_377del - most up to date transcript

ClinVarID: N/A

CAID: CA913189240 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.371_377delCACACGA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: G123fs (c.369_375delGACACAC)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.256C>T), affecting residue within the pVHL protein core, was found in a VHL patient with cerebellar hemangioblastomas diagnosed at 35Y. ACMG codes as follows: Supporting evidence of pathogenicity because missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2).

GroupID: 20

Case: 19Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: retinal capillary hemangioma

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: patient had retinal angiomas diagnosed at 19Y

CaseNotHPOs: HP:0005584; HP:0002666; HP:0006880 (renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.T124Hfs*35 (c.369delG)

LegacyVariant: p.Thr124Hisfs*35 (c.367delG)

CaseProblemVariantFreeText: c.367delG automaps to c.369delG - most up to date transcript

ClinVarID: N/A

CAID: CA432421810 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.369delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: T124fs (c.369del)

MultipleGeneVariants: N/A

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. SSCP analysis found a p.R167W (c.499C>T) mutation, stated in the paper as c.712C>T due to an older transcript. It was seen in family 3, with one member affected with pheochromocytoma which was said to detect loss of heterozygosity for a PstI polymorphism within the gene. Family 3 consisted of 3 VHL-affected members: a mother and her two daughters.

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. RT-PCR analysis in RCC cell lines found a p.I180N (c.539T>A) mutation, stated in the paper as c.752T>A due to an older transcript. It was seen in 2 cell lines: A-704 and 769-P. Any family information or other manifestations apart from RCC were unclear.

A 74 year old man was confirmed to have the germline mutation (p.Glu70Lys (c.208G > A)). He had a history of arterial hypertension and retinitis causing loss of vision and amblyopia in the right eye. It was presumed that he might have had retinal hemangioblastoma in the past. MRI found a spinal hemangioblastoma and whole body PET scan lead to a diagnosis of renal cell carcinoma. Colonoscopy lead to the diagnosis of colorectal adenocarcinoma. Brain MRI showed cerebellar hemangioblastomas. Histologic examination of liver revealed a metastatic adenocarcinoma. The patient's mother was diagnosed with a brain tumour of unconfirmed pathology. Both his brothers (ages 70 and 79) were confirmed to have the mutation and presented with renal cell carcinoma. The patient's 44 year old son was confirmed with the mutation but was asymptomatic. His daughter was noted as having a brain hemorrhage and his niece a hematologic malignancy.

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

GenotypingMethod: N/A

SamplingMethod: N/A

PatientID: 145

KindredID: None

Case: Age and Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0001737; HP:0000107; HP:0005584; HP:0030405 (pancreatic cysts, renal cyst, Renal cell carcinoma, Pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666; HP:0030393 (hemangioblastoma, Retinal capillary haemangioblastoma, Pheochromocytoma, Endolymphatic sac tumour)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; See Suppl 1 (Supporting table)

Variant: c.464-?_642+?del

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

ArticleReferenceSequence: NM_000551 (version not specified, assumed to be NM_000551.3)

GenotypingMethod: polymerase chain reaction (PCR)

SamplingMethod: peripheral blood using using the QIAamp DNA Blood Mini kit (Germany)

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France). No variants were found in 96 control cases. This missense mutation, c.482G>A, was found in four unrelated VHL type 2A patients (patients V32, V60, V97). Patient V32's family member also had this mutation. These four patients presented with pheochromocytoma. Type 2A VHL families were described as having pheochromocytomas.

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 P71Lfs*61 (c.211_212insT) mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V96).

GroupID: V13

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: Patients are grouped by family.

FamilyInfo: 4/8 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.W117C (c.351G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified- Assumption: Nucleotide change is not specified in the paper, only protein coding change is. cDNA variant was inferred based on protein coding change, and reported based on VHL reference sequence NM_000551.3

GenotypingMethod: Sequenced using Bigdye Terminator V3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA, USA). Products were analyzed on the ABI Prism 3100 genetic analyzer (Applied Biosystems).

SamplingMethod: tumour tissue

GroupID: 23A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L163H (c.488T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756137 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L163H (c.488T>A)

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. 160 patients were found to have the above mutation (c.292T>C). 2 were VHL patients with ICTs (pancreatic neuroendocrine tumors) taken from the VHL-registry. The other 158 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: 24B

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: 15

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 15 patients with the given mutation were grouped as group 24(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: 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

GroupID: 28B

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

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 patients with the given mutation were grouped as group 28(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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA70052558 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.583C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PMID: 31620170

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 2

KindredID: 2 (group ID 5)

Case: F, 45Y0M (deceased), Chinese

DiseaseAssertion: assumed VHL

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

FamilyInfo: In family 2, 4 members were described in a 3 generation family. The patient’s father, brother, and daughter were also present with the VHL mutation. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: HP:0002894 (neoplasm of the pancreas)

CaseHPOFreeText: She had passed away with pancreatic cancer

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

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.L89P (c.266T>C) mutation, 11 members total from 2 families were described, and phenotypic information was given for this group. With ages ranging from 15-52Y, hemangioblastomas were observed in 6/11 members, retinal capillary hemangioma in 5, renal cell carcinoma in 6, pancreatic cysts in 4, and pheochromocytoma in 1 member. See more information as this cohort has been previously published in PMID 29330336; 28388566.

PatientID: 3

KindredID: 1 (group ID 5)

Case: M, 63Y0M (deceased), Chinese

DiseaseAssertion: assumed VHL

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

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 3’s two sons were passed this familial mutation. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: He had CNS hemangioblastomas at 62Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S5 describes 8 patients with small deletions, including this patient.

Variant: p.L129Wfs*30 (c.384del)

LegacyVariant: c.597delT (p.128fs)

CaseProblemVariantFreeText: Submitted revision on CIViC for correct CIViC name: L129Wfs*30 (c.384del).

ClinVarID: N/A

CAID: CA70049452

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant; deletion

CivicName: L129Wfs*?(c.383delT)

MultipleGeneVariants: N/A

The authors described the growth kinetics of 96 renal tumours in 64 VHL patients (32 males, 32 females). All patients had VHL disease with renal involvement. 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 patients, at least one or more RCC was diagnosed. However, at the time of diagnosis, an indication for treatment was not yet present. For all patients, several CT/MRI scans existed for retrospective description of tumour growth kinetics. 10-ml EDTA anticoagulated blood samples were available from each patient for mutation screening of all exons of the VHL gene. Genomic DNA from blood samples was extracted using standard methods. Small deletions/insertions or point mutations were identified by DNA sequencing followed by complete mutation screening using PCR/single-strand conformation polymorphism and denaturing high-performance liquid chromatography. A germline deletion p.R177Dfs*25 (c.528del) was identified in patient #49. This mutation was noted as c.740delG in the paper due to a difference in reference transcript used (see Table S5). No family information is available for this patient.

PatientID: 2

KindredID: 2

Case: M, 40Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: N/A - family history was unremarkable. The paper states however that this patient inherited the duplication from a nonsymptomatic parent. Two siblings of patient 2, aged over 40 and also carriers of the same variant, underwent a thorough clinical evaluation, which was judged as negative.

CasePresentingHPOs: HP:0006880; HP:0011798 (cerebellar hemangioblastoma, renal oncocytoma)

CaseHPOFreeText: a 40-year-old male affected by cerebellar hemangioblastoma and renal oncocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21463266

SupplementalData: N/A

Variant: c.–65_–55dup11

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 517152 https://www.ncbi.nlm.nih.gov/clinvar/variation/517152/

CAID: N/A

gnomAD: 0.00009581 https://gnomad.broadinstitute.org/variant/3-10183466-C-CTCCGCCCCGCG

VariantEvidence: Quantitative Southern blot/real-time quantitative PCR analyses was normal in this patient. The 11 bp duplication is located within the promoter region of the VHL gene, in the vicinity of the main transcription initiation site, and within the binding site of several transcription factors. There is a possibility that the variant could alter transcription of the gene from the affected allele.

MutationType: 5_prime_UTR_variant

CivicName: c.–65_–55dup11

MultipleGeneVariants: N/A

Germline mutations were found in 20 Brazilian, VHL probands and their families. The V130F (c.388G>T) germline missense mutation was found in a VHL type 1 family of 14 affected individuals (VHL family 11). Seven patients had hemangioblastomas of the central nervous system, 2 with retinal angiomas, and one with renal carcinoma and pancreatic cystadenoma. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

GroupID: 8

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 2 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

GroupHPOFreeText: CNS hemangioblastoma (2/2 affected members).

GroupNotHPOs: HP:0009711; HP:0002894; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Neoplasm of the pancreas, Pheochromocytoma, Renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+7G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131791, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131791

gnomAD: N/A

VariantEvidence: Variant reported as IVS1+7G>A which is assumed to be equivalent to c.340+7G>A. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

MutationType: splice_site_variant; missense_variant;transition

CivicName: c.340+7G>A

MultipleGeneVariants: N/A

PatientID: None (Mother)

KindredID: 13

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Child of this patient presented with CNS hemangioblastoma, retinal angioma, renal carcinoma and a renal tumor <3cm in size and the c.436delC germline variant of the VHL gene.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0001737 (Cerebellar hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: This patient was originally thought to be an asymptomatic carrier but was later discovered to have two occult hemangioblastomas (spinal and cerebellar) as well as multiple pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P146Lfs*13 (c.436del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421892, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.436del

gnomAD: N/A

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

MutationType: deletion; minus_1_frameshift_variant

CivicName: P146fs (c.436del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: M, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: He had a daughter who has heterozygous for the mutation.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

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: The patient had a mosaic mutation with a mutated allele frequency of 1.7%. The right renal cell carcinoma was analyzed and found to have a mutated allele frequency of 11.1%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 231

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states familial VHL

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

CaseHPOFreeText: Patient had CNS HB, pancreatic cysts, and a Grawitz tumor

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

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

PMID: 20151405

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 5

KindredID: 6

Case: F, 40Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had a hemangioblastoma localized to the corpus callosum at age 31. After surgery the patient was alive with disease. The patient was followed up 108 months later.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion

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

PMID: 20647972

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 9124215

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: Proband 3

KindredID: 1

Case: M, 17Y0M, Chinese

DiseaseAssertion: VHL

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: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral PCC diagnosed at 17Y and did not have any other clinical presentations. Stated as having VHL type IIC.

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

PatientID: Proband 6

KindredID: 2

Case: F, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Mother, aunt and aunt’s cousin (all relative to proband 6) had this variant. Mother and proband presented with unilateral pheochromocytoma and aunt and aunt’s cousin were asymptomatic. Proband also presented with a renal cyst and hypertension.

CasePresentingHPOs: HP:0002666; HP:0000107; HP:0000822 (Pheochromocytoma, Renal cyst, Hypertension)

CaseHPOFreeText: Unilateral PCC diagnosed at 28Y and unilateral renal cyst and hypertension. Stated as having VHL type IIC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R120T (c.359G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753738, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.359G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R120T (c.359G>C)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 3

Case: F, 18Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: Another member of this family (Gen 1) presented with the same mutation and bilateral pheochromocytoma, pancreatic cysts, RCC and neural hemangioblastoma.

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:0010797; HP:0002668; HP:0030405; HP:0001737 (Pheochromocytoma, Hemangioblastoma, Paraganglioma, Pancreatic endocrine tumor, Pancreatic cysts)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma. Cause of death: adrenal crisis.

CaseNotHPOs: HP:0009711; HP:0005584 (Retinal capillary hemangioma, 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

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 (E186del (c.558_560del)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 113CA. It was reported in the paper as c.771_773delGlu due to a difference in transcript reference. Table 5 lists all ID and mutations associated with individuals without detailed clinical information. Other phenotypes are possible, however not detailed here.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (Y175* (c.525C>G)) was taken from the Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 63F. It was reported in the paper as c.738C>G due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 133CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 133CA. 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.G114C (c.340G>T)

LegacyVariant: p.G114C (c.553G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751376 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G>T

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G114C (c.340G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4479NCI, 50CE

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database as well as the Munich, university of Freiburg and Institude of Pathology database, with an unknown number of members belonging to Family ID 4479NCI and 50CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL families 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: 8707293

SupplementalData: N/A

Variant: p.E70* (c.208G>T)

LegacyVariant: p.E70* (c.421G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 428806 https://www.ncbi.nlm.nih.gov/clinvar/variation/428806/

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: E70* (c.208G>T)

MultipleGeneVariants: N/A

GroupID: 146

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

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

LegacyVariant: c.564G>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

PatientID: V-11

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: V-21

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma, Paraganglioma, Retinal capillary hemangioma)

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient). Deceased.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: VI-17

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666; HP:0002668 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma, Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

KindredID: 103

GroupID: 14

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.103 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: No other phenotypic information is listed for this kindred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80R (c.240T>G)

LegacyVariant: p.S151R (c.453T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750515

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S80R (c.240T>G)

MultipleGeneVariants: N/A

KindredID:71

GroupID: 10

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.71 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is present in this kindred.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: This study investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. No other information about disease presentation within members of a kindred could be inferred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C77Lfs*55 (c.228dup)

LegacyVariant: c.441insC (p.147fs)

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795177, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.228_229insC

gnomAD: N/A

VariantEvidence:

MutationType: plus_1_frameshift_variant; duplication

CivicName: C77Lfs*55(c.228dup)

MultipleGeneVariants: N/A

A 12Y male African-American patient presented with hypertension and intermittent headaches and was found with multiple bilateral pheochromocytoma, a systolic heart murmur, left ventricular hypertrophy and heart block. He had a history of congenital microcephaly, severe hearing loss, developmental delay, and cryptorchidism. Genetic analysis confirmed a c.238A>G (p.Ser80Gly) germline mutation in the VHL gene, but this mutation was not found in the parents suggesting a de novo mutation. He had no other notable family history. There was no history of polyuria, polydipsia, tachycardia, or sweating. Exams showed normal head morphology and no neurological abnormalities, normal sinus rhythm, no evidence of coarctation of the aorta or other structural anomalies, no evidence of papilledema, hemorrhages, exudates, retinal angiomas, or focal neurological signs. He was also negative for abdominal organomegaly, abdominal bruits, renal parenchyma abnormalities, hydronephrosis and cystic lesions or tumors of the pancreas.

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma and RCC.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: codon 147 (c.440delTCT)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: Nucleotide deletion (i.e. 440delTCT) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.227_229del (NM_000551.3).

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

150 index patients with pheochromocytoma/paraganglioma were evaluated. Phenotypic data were collected and germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested. Out of 30 patients with familial presentation, 13 were clinically diagnosed as VHL syndrome. Using PCR and Sanger sequencing through peripheral blood, genetic testing confirmed a non-familial missense mutation at c.533T>A of the VHL gene in two unrelated patients. The first was a 21 year old Asian Indian male who presented with unilateral pheochromocytoma. Family history is unknown, it was apparently sporadic. The second was a 14 year old Asian Indian male who presented with bilateral pheochromocytoma. He had a positive family history.

PatientID: 28

KindredID: 28

Case: F, 32Y0M, Asian Indian

DiseaseAssertion: pheochromocytoma

FamilyInfo: None - Apparently sporadic

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Unilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.341-2A>G

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223194 https://www.ncbi.nlm.nih.gov/clinvar/variation/223194/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.341-2A>G)

MultipleGeneVariants: N/A

PatientID: III:1

KindredID: 1

Case: M, 6Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Case III:1 (this patients mother) was a 32 year old female who complained of blurred vision for the past 2 years in her left eye. Fundus examinations showed several retinal hemangioblastomas in the temporal area of the left eye. They had previously undergone the operation for cerebellar hemangioblastoma 3 years prior. Case III:2 (this patient’s sister) was a 12 year old female who complained of a curtain coming across the vision in her left eye during the screening examination. Fundus examinations revealed a small hemangioblastoma in the infratemporal region of the peripheral retina in her right eye. A sizeable hemangioblastoma with 2.5 papilla diameters and prominant feeder vessels were detected in the inferior peripheral retina of her left eye. Case I:2 (this patient’s grandmother) had blindness in one eye and died of renal carcinoma, genetic testing was not preformed on this patient. Pedigree: see Figure 1.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Fundus examination revealed a very small hemangioblastoma in the distant peripheral retina of his right eye, while his left eye was normal.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753664 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: M, 24Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: (See figure 3C for pedigree). Family history of VHL. The proband (Patient 3) of family 3 was a 24-year-old male who presented with adrenal pheochromocytomas and a cyst in his left kidney. The proband's family history of VHL included a mother and aunt who died from brain hemangiomas, a sister with pheochromocytomas in her bilateral adrenals and a female cousin with pheochromocytomas in her right adrenal.

CasePresentingHPOs: HP:0006748, HP:0000107 (Adrenal pheochromocytoma, Renal cyst)

CaseHPOFreeText: Masses in his bilateral adrenals (pheochromocytomas). In February 2013, he underwent an abdominal CT scan that revealed masses in his bilateral adrenals (Fig. 1C, upper image) and a cyst in his left kidney.

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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

Genotype-phenotype correlations were analyzed in five unrelated Chinese families with a family history VHL. The proband (Patient 3) of family 3 was a 24-year-old male who presented with adrenal pheochromocytomas and a cyst in his left kidney. The proband's family history of VHL included a mother and aunt who died from brain hemangiomas, a sister with pheochromocytomas in her bilateral adrenals and a female cousin with pheochromocytomas in her right adrenal. Genetic analysis of the proband was done using DNA isolated from peripheral blood and was screened for potential mutations in a panel of susceptibility genes for pheochromocytoma’s and/or RCC using Target Capture-Based Deep Sequencing. Identification of mutations were further screened by Sanger Sequencing. In the proband, a mutation in VHL was confirmed: c.500G>A (p.Arg167Gln). The same mutation, c.500G>A (p.Arg167Gln), was also found in the proband (Patient 4) from an unrelated family (family 4). The proband was a 21-year-old male who reported blurry vision and metamorphopsia in his left eye for 10 days. Tissue pathology revealed a hemangioblastoma in his left retina. After 8 months, he presented with masses in his bilateral adrenals. Pathological report confirmed the presence of pheochromocytomas. Additionally, an MRI scan showed a mass in his basal ganglia region , a mass in his left frontal lobe, as well as a mass in his cervical cord, which were most likely CNS hemangioblastomas, but were not confirmed with pathological investigation. The proband's family history of VHL included his father who also had pheochromocytomas in his bilateral adrenals.

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. Two patients with VHL-related retinal angiomatosis were found to have germline missense (c.548C>A) mutation in the VHL gene. This variant was reported as c.761C>A (AF010238.1) and mapped to p.S183* (c.548C>A) (NM_000551.3).

PatientID: None (Brother)

KindredID: 24

Case: M, 27Y0M, EthnicityUnknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 2/3 genetically tested individuals from a family with no family history of VHL disease were found to harbor the c.492G>T mutation causing a Gln164His missense variant (noted in the paper as c.705G>T due to Latif reference transcript being used). The proband presented with retinal capillary hemangioma and the other had unremarkable ophthalmoscopic findings (27Y, brother). The proband’s sister was negative for the variant.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Paper states that ophthalmoscopic findings were unremarkable.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164H (c.492G>T)

LegacyVariant: c.705G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 456566, https://www.ncbi.nlm.nih.gov/clinvar/variation/456566/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Q164H (c.492G>T)

MultipleGeneVariants: N/A

PatientID: 30

KindredID: 3407

Case: M, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 31) presented with one radiologic pancreatic neuroendocrine tumor and had the same VHL gene mutation.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with one radiologic pancreatic endocrine tumour.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167W (c.712C>T)

CaseProblemVariantFreeText: N/A

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

CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET

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: 43

KindredID: 5959

Case: F, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with four pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: p.P81S (c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVar: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: CA020148 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.241C%3ET

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81S (c.241C>T)

MultipleGeneVariants: Germline, VHL, c.562C>G (p.Leu88Val)

PatientID: 50

KindredID: 17

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with multiple pancreatic cysts/tumors and renal cell carcinoma at 30.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, 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.L85P (c.254T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 376222; https://www.ncbi.nlm.nih.gov/clinvar/variation/376222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L85P (c.254T>C)

MultipleGeneVariants: N/A

PatientID: 131

KindredID: 49

Case: F, Age 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a pheochromocytoma at 18, retinal angioma at 29, and renal cell carcinoma and multiple pancreatic cysts/tumors at 31.

CaseNotHPOs: HP:0010797 (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.F136C (c.407T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496065; https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

PatientID: 54

KindredID: 19

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 54) has a daughter who was genetically confirmed with the same mutation. The daughter was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband presented with a retinal angioma at 12, renal cell carcinoma and multiple pancreatic cysts/tumors at 33.

CaseNotHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: 231

KindredID: 86

Case: M, 54Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 229) had a sister (patient 230) who was genetically confirmed with the mutation, and presented with a CNS hemangioblastoma at age 40. The proband's brother 1 (patient 231) was also confirmed with the mutation and had a retinal angioma at 25, and renal cell carcinoma at 54. The proband's brother 2 passed away before they could be diagnosed/ confirmed with the mutation, but they had a CNS hemangioblastoma at 35. Finally, the proband's nephew (son of brother 2) was genetically confirmed with the mutation and presented with renal cell carcinoma at age 30.

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

CaseHPOFreeText: The proband's brother (patient 231) had a retinal angioma at 25 and renal cell carcinoma at 54.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0001737; HP:0001732 (Hemangioblastoma, Pheochromocytoma, 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.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: 2

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: Retinal hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (Retinal hemangioblastoma)

CaseHPOFreeText: The patient was diagnosed with bilateral retinal hemangioblastoma at an unknown age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.*214Lext*14(c.641G>T)

LegacyVariant: N/A

ClinVarID: 223236, http://www.ncbi.nlm.nih.gov/clinvar/variation/223236

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_loss

CivicName: *214Lext*14(c.641G>T)

MultipleGeneVariants: N/A

A 42 year old Chinese male presented with cerebral hemangioblastoma, clear cell renal cell carcinoma, and an epididymal tumour. PCR testing of peripheral blood confirmed two familial mutations, a missense (c.256C > T) and a splice site mutation (c.340+5G>C) of the VHL gene. The patient has a 34 year old sister with the same mutations who presented with cerebral hemangioblastoma, pancreatic cysts, and liver cysts.

PatientID: 1

KindredID: 1

Case: F, 35Y0M, Japanese

DiseaseAssertion: VHL

FamilyInfo: No relevant family history - speculated de novo but did not perform genetic testing of family members

CasePresentingHPOs: HP:0002894; HP:0005584; HP:0006880 (pancreatic neoplasm; renal cell carcinoma; hemangioblastomas of the cerebellum)

CaseHPOFreeText: A 35Yo woman became aware of a tumour - giant masses in the whole pancreas and a tumor of the right kidney - after giving birth to a healthy boy. History of cerebal hemangiomas treated by surgery 14Y previously (at 21 years old). (serous cystic neoplasms pancreas; Right renal cell carcinoma; hemangioblastomas of the cerebellum)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N78I (c.233A>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: Not specified

SamplingMethod: Not specified

PatientID: 10 (Uncle)

KindredID: 7

Case: M, 36Y0M, 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 1 presented with pheochromocytoma. ID 2 presented with pancreatic abnormalities. ID 24 presented with renal abnormalities, and pheochromocytoma, and died at age 62. ID 4 presented with pheochromocytoma.

CasePresentingHPOs: HP:0002666; HP:0001732; HP:0010797 (Pheochromocytoma, Abnormality of the pancreas, Hemangioblastoma)

CaseHPOFreeText: The patient presented with CNS hemangioblastoma (31Y, 35Y), pancreatic abnormalities (31Y) and pheochromocytoma (13Y).

CaseNotHPOs: HP:0009711; HP:0005584; HP:0000077 (Retinal capillary hemangioma, Renal cell carcinoma, 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

PatientID: 1 (Proband)

KindredID: 1

Case: M, 20Y0M, 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 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). ID 21 presented with retinal angioma and pheochromocytoma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a Pheochromocytoma at age 11.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0000077; HP:0010797 (Retinal capillary hemangioma, 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