PatientID: None

KindredID: 1

Case: M, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No notable family history.

CasePresentingHPOs: HP:0000541; HP:0010797; HP:0009711; HP:0030424; HP:0005562; HP:0001737 (Retinal detachment, Hemangioblastoma, Retinal capillary hemangioblastoma, Epididymal cyst, Multiple renal cysts, Pancreatic cysts)

CaseHPOFreeText: Complained of a shadow in his right eye and was diagnosed with retinal detachment secondary to a retinal hemangioblastoma. MRI of the brain revealed a hyper vascular lesion in the medulla and a smaller lesion at the medullary-spinal cord junction. Weighted abdominal MRI revealed innumerable pancreatic cysts and multiple benign-appearing renal cysts. After surgical resection of the retinal hemangioblastoma, the patient remains asymptomatic.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.K159* (c.474_475insT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423112, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.474_475insT

gnomAD: N/A

VariantEvidence: Reported as: NT474INST. Authors state that this is believed to be a novel sporadic mutation.

MutationType: insertion; plus_1_frameshift_variant; stop_gained

CivicName: K159* (c.474_475insT)

MultipleGeneVariants: N/A

GroupID: 8

Case: 37Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: patient had retinal angiomas diagnosed at 28Y, cerebellar hemangioblastomas diagnosed at 22Y, and renal cell carcinoma diagnosed at 37Y.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

PatientID: 280

KindredID: 110

Case: M, 22Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22. Their father presented with a CNS hemangioblastoma at age 25, and retinal angioma at age 29.

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

CaseHPOFreeText: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: 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: 47

KindredID: 15

Case: F, 22Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (oatient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52.

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

CaseHPOFreeText: The proband's niece 1 (patient 47) had a retinal angioma and renal cell carcinoma at 22.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0002666; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, 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.S80Tfs*77 (c.239_245del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189246; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239_245del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239_245del)

MultipleGeneVariants: N/A

PatientID: III-9

KindredID: 1

Case: F, 32Y0M, 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. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000541; HP:0002542; HP:0001737; HP:0000107; HP:0030405; HP:0001272; HP:0007366; HP:0010873; HP:0001251; HP:0001260; HP:0001310 (hemangioblastoma, Retinal capillar hemangioma, Retinal detachment, Olivopontocerebellar atrophy, Pancreatic cysts, Renal cyst, Pancreatic endocrine tumor, Cerebellar atrophy, Atrophy/Degeneration affecting the brainstem, Cervical spinal cord atrophy, Ataxia, Dysarthria, Dysmetria)

CaseHPOFreeText: diagnosed with VHL in her early teenage years. She had retinal involvement beginning at the age of 13 treated by cryotherapy and laser therapy (presumably for retinal angiomas); and retinal detachment at the age of 23 requiring eye surgery. She had cysts of the pancreas and kidney detected at 22 years. She has also carried the diagnosis of OPCA since the age of 26-28 (new onset slurred speech and illegible handwriting). Patient had multiple renal cysts without renal tumours, however a large infiltrative enhancing mass in the tail of the pancreas was suggestive of a neuroendocrine/islet cell carcinoma, and liver metastatic foci

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: 24 (Aunt)

KindredID: 18

Case: F, 80Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (36Y), pheochromocytoma (36Y) and retinal angioma (22Y).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

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

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

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

PatientID: 7

KindredID: 7

Case: 23Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Thus far, it has not been possible to study the parents or close relatives of this patient.

CasePresentingHPOs: HP:0009711; HP:0000107 (retinal capillary hemangioma; renal cyst)

CaseHPOFreeText: Aged 22Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. Bilateral retinal hemangioblastomas diagnosed at 22Y, and renal cysts were diagnosed at 23Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q132Hfs*45 (c.343_395dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497030272 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497030272

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant; duplication

CivicName: Q132Hfs*45 (c.343_395dup)

MultipleGeneVariants: N/A

PatientID: III:2 (case)

KindredID: 1

Case: F, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: VHL disease was diagnosed in her relatives - although no genetic testing was directly performed on them prior to death. 2/3 of her siblings and her father were affected. Her father had retinal hemangioblastoma at 30Y, CNS hemangioblastoma at 40Y and died at 41Y. Her older brother had kidney cancer and died at 48Y, and her sister had retinal hemangioblastoma at 13Y and CNS hemangioblastoma at 29Y. The case’s daughter tested negative and their other living sister.

CasePresentingHPOs: HP:0009711; HP:0000107; HP:0009713; HP:0002668 (retinal capillary hemangioblastoma; renal cysts; spine hemangioblastoma; paraganglioma)

CaseHPOFreeText: patient at retinal hemangioblastoma at 22Y. At 47Y she reported pains in her second and third finger of the right hand. She developed large carotid body paraganglioma at the common carotid artery bifurcation, (49Y) coexisting with a hemangioblastoma situated intramedullary in region C5/C6 (the right-sided dorsal part of the spinal cord) at 47Y). 1 year after the hemangioblastoma resection, the spinal symptoms receded and the carotid body paraganglioma still was asymptomatic. Motor issues and Babinski syndrome were also observed.

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

PatientID: 83 (Cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (25Y), retinal angioma (16Y) and pancreatic tumors or cysts (undefined) (22Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II:3 (proband 4)

KindredID: 4

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s mother (I:1) was found with the same mutation and RCC at 63Y. The proband’s brother (II:1) died before diagnosis; thus no DNA sample available. He presented with hemangioblastoma at 19Y

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

CaseHPOFreeText: patient had hemangioblastoma at 22Y and retinal capillary hemangioma at 32Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N90I (c.269A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223172 https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: IV-13

KindredID: 1

Case: F, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The patient had an affected brother (IV-14) who carried the Ser80Asn mutation and presented with pheochromocytoma and retina hemangioblastoma. The patient's mother (III-7) carried the same mutation and had a brain hemangioblastoma and retina hemangioblastoma. The uncle (III-8) harboured the same mutation and had brain hemangioblastoma, pheochromocytoma, and retina hemangioblastoma. He had three kids, out of which only one carried the mutation but was asymptomatic (IV-16). The patient's grandmother (II-5) also harboured the same mutation and presented with renal cell carcinoma. This patient's great aunt (II-1) carried two different VHL mutations; the Ser80Asn and Pro25Leu but herself was asymptomatic. She passed the Ser80Asn mutation to her daughter, the proband (III-1), who had renal cell carcinoma, brain hemangioblastoma, and pheochromocytoma. Refer to figure 1 for pedigree.

CasePresentingHPOs: HP:0010797, HP:0009711, HP:0000107 (hemangioblastoma, retinal capillary hemangioma, renal cyst)

CaseHPOFreeText: The patient presented with brain hemangioblastoma at age 22, retina hemangioblastoma at age 23, and renal cysts at age 20.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80N (c.239G>A)

LegacyVariant: p.S80I (c.239G>A) *author mistake

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70046108 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 11

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.T157I

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: M, 22Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

CohortInfo: Case series of 14 patients with definite or presumed von Hippel-Lindau disease and retinal vascular proliferation.

CasePresentingHPOs: HP:0002011, HP:0001732, HP:0007850, HP:0012210, HP:0009711 (Morphological central nervous system abnormality, abnormality of the pancreas, retinal vascular proliferation, abnormal renal morphology, retinal capillary hemangioma)

CaseHPOFreeText: At age 12, his left eye had a large juxtapapillary vascular complex extending from the nerve along the superior arcade that was associated with dense fibrovascular tissue. During the next 29 months, this fibrovascular complex enlarged, extending into the center of the macula and causing a decrease in visual acuity to 20/80. The patient underwent pars plana vitrectomy and membrane peel. When the patient was reexamined 7 years after his surgery, there was no recurrence of the lesion. In the patient's contralateral right eye, 3 typical peripheral RCHs were observed during this 7-year follow-up. At age 14 years, he was also noted to have a small patch of superficial retinal vessels in the inferior retinal quadrant near the equator of the right eye that resembled an arteriovenous anastomosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName:Null (Partial deletion)

MultipleGeneVariants: N/A