PatientID: None (Grand Cousin 1)

KindredID: G

Case: Sex Unknown, 23Y0M, Hungarian

DiseaseAssertion: Assumed VHL

FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005562 (Hemangioblastoma, Retinal capillary hemangioma, Multiple renal cysts)

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 22 and retinal hemangioblastoma at age 23. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as S80I and cDNA change was mapped to c.239G>T.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

GroupID: 61

Case: Age Unknown, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.262T>A) 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 angioma diagnosed at 23Y, cerebellar hemangioblastoma diagnosed at 54Y, and RCC at 54Y.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

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: 288

KindredID: 113

Case: M, 24Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 288) presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 23, and a retinal angioma at 24. Their sister (patient 289) presented with a CNS hemangioblastoma, retinal angioma, and renal cell carcinoma at 30.

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

CaseHPOFreeText: The proband (patient 288) presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 23, and a retinal angioma at 24.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 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: N/A

KindredID: 1

Case: M, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Genetic analysis of the patient's parents and brothers, who were unaffected, confirmed a diagnosis of de novo VHL disease.

CasePresentingHPOs: HP:0030424, HP:0009711, HP:0005584, HP:0006770, HP:0001737, HP:0000107 (epididymal cyst, retinal capillary hemangioma, renal cell carcinoma, clear cell renal cell carcinoma, pancreatic cysts, renal cyst)

CaseHPOFreeText: He was admitted to the hospital with a two-month history of progressive right flank pain, accompanied by a one-month history of recurrent painless gross hematuria. The patient's previous medical history included urological surgery at the age of 23 years due to an epididymal cyst and an ophthalmologic surgery at 26 years of age for retinal detachment resulting from bilateral retinal angiomatosis. Contrast-enhanced computed tomography (CT) scanning and angiography were used to detect the presence of quasi-circular enhancing lesions in the middle of the left kidney and large irregular enhancing lesions in the right kidney, extending into the vena cava, that formed an embolus. In addition, multiple cysts in the pancreas and kidney were detected radiologically. The patient underwent a radical nephrectomy with an embolectomy of the right kidney for treatment of T3b-stage renal cell carcinoma. After three months, he successfully underwent laparoscopic nephron-sparing surgery (NSS) of the left kidney. Histological analysis of the renal tissue revealed clear cell carcinomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S65W(c.194C>G)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: assumed VHL

GroupSize: 15

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 36.9Y +/- 15.6Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 3 families with 15 members total were described, and phenotypic information was given for this group.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, pheochromocytoma)

GroupHPOFreeText: 10 of the 15 members presented with CNS hemangioblastoma (mean age of 29.9Y), 2/15 had retinal capillary hemangiomas at 23Y and 30Y, renal cell carcinoma in 4 members (at a mean age of 41.5Y), pancreatic cysts in 5 members (with a mean age of onset of 41.4Y), and 1 member with pheochromocytoma at 38Y

GroupNotHPOs: HP:0009715 (papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No patients were given with papillary cystadenoma of the epididymis

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336; 28388566

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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;transition

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

GroupID: 15

Case: 23Y0M, 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:0009711; HP:0006880 (retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: patient had retinal angiomas at 21Y and cerebellar hemangioblastomas diagnosed at 23Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.F91* (c.272_273delinsAA)

CaseProblemVariantFreeText: c.272T>A and c.273C>A results in c.272_273delinsAA

LegacyVariant: N/A

ClinVarID: CA2499307077 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307077

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins; stop_gained

CivicName: F91* (c.272_273delinsAA)

MultipleGeneVariants: N/A