2 affected; 2 rHAB, 1 cHAB, 1 pheo between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 24 has 2 affected members. Genetic analysis reveals mutation Q195*(c.583C>T) in the VHL gene. The patients have a family history of VHL disease. Of the 2 affected members, 2 members had retinal capillary hemangioma, 1 member had CNS hemangioblastoma, 1 member had pheochromocytoma. ACMG: 'PP4' because the patient's phenotype and family history are highly specific for a disease with single genetic etiology.

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 30 has 1 affected member. Genetic analysis reveals the mutation C162Wfs*12(c.485dupG) in the VHL gene, which the paper reports in less up-to-date as c.485dupG (p.L163fs). The patient was said to be sporadic in their history of VHL disease. They have CNS and retinal hemangioblastomas.

PatientID: 10

KindredID: 10

Case: 30Y0M, 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:0010797; HP:0006770; HP:0000107 (hemangioblastoma; clear cell renal cell carcinoma; renal cysts)

CaseHPOFreeText: Aged 29Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS hemangioblastoma diagnosed at 29Y, ccRCC and renal cysts were diagnosed at 30Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Q73Pfs*59 (c.217dupC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497030271 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497030271

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: Q73Pfs*59 (c.217dupC)

MultipleGeneVariants: N/A

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation was detected by direct sequencing and MLPA. This nonsense mutation (p.F148* (c.443_455delinsA)) was found in as a sporadic germline in a VHL case with multiple bilateral retinal angiomas (case no. 401). The case was suspected to be de novo but this could not be confirmed. There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1).

PatientID: N/A

KindredID: 401

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states: Germline, de novo (no clear confirmation)

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: multiple bilateral retinal capillary hemangiomas

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: p.F148* (c.443_455delinsA)

LegacyVariant: N/A

CaseProblemVariantFreeText: stated as a p.F148fs (del/ins/FS), however stop_gained rather than frameshift is the protein result

ClinVarID: N/A

CAID: CA2573050544 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573050544

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName: F148* (c.443_455delinsA)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 18Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history involved.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: 'Other' phenotypes found in patient. These are noted in the paper to include: pancreatic neuroendocrine tumors (PNETs), renal and pancreatic cysts and central nervous system tumors, although it is not clearly stated that patient 1 has all. (See Table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P59Afs*73 (c.173_174insC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: CA658795188 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.173_174insC

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P59Afs*73 (c.173_174insC)

MultipleGeneVariants: N/A

A case report of a 46Y old Chinese male VHL patient presenting with multiple clear cell renal cell carcinoma at the age of 43 is described. Additional manifestations included renal and pancreatic cysts. Molecular analysis through peripheral blood confirmed the presence of the (c.302T>G) mutation. Family history showed a clinical diagnosis of VHL in the father and sister who had the following manifestations: CNS hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumor, and renal cysts. See PMID: 24112165 for more information on this family.

PatientID: 1

KindredID: 1

Case: M, 46Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: known family history of VHL - His father, who had neoplasm and cyst in both kidneys, died of HB-CNS at 50 years old; and his sister was found to have neoplasm in both her pancreas and kidney. Explicit mutations or testing was not mentioned. In PMID: 24112165, these two members are confirmed with the mutation.

CasePresentingHPOs: HP:0006770; HP:0000107; HP:0001737; HP:0001407 (clear cell carcinoma; kidney cysts; pancreatic cysts; hepatic cysts)

CaseHPOFreeText: discovered to have signal abnormalities in his left kidney, liver and pancreas in a computed tomography (CT) evaluation - 2 tumors, one upper and one middle pole of the left kidney, as well as a cyst was found. At 43Y he was diagnosed with ccRCC in the right kidney via a hematuria and right-side lumbago.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24112165

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: B

Case: Sex Unknown, 26Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: 6 members in this family presented with the mutation. 2 were asymptomatic (ages 2 and 7Y). Other family manifestations include: cerebellar, spinal, bulbar, retinal HBs, pancreatic and kidney cysts, and RCC.

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0001737; HP:0000107;H P:0005584 (cerebellar hemangioblastoma, retinal capillary hemangioma, pancreatic cysts, renal cysts, renal cell carcinoma)

CaseHPOFreeText: Patient had 1 cerebellar HB, bilateal retinal angiomas, pancreatic & kidney cysts, RCC

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: C

Case: Sex Unknown, 21Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

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

CaseHPOFreeText: Patient had epididymal cystadenoma. They however appeared absent of clinical manifestations of VHL disease prior to clinical and imaging scrutiny.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

Analysis of peripheral blood samples from 5 Japanese families with PCR and SSCP revealed 4 germline mutations. This missense mutation NM_000551.3:c.484T>C was found in a family of seven individuals. Please note that the paper states the mutation as c.697T>C because it uses a legacy reference sequence. Two VHL patients were identified; the patients were siblings, and one presented with brain stem hemangioblastomas and retinal angiomas while the other presented with renal cell carcinoma (family D). Single-strand conformational polymorphism (SSCP) analysis showed bands for the 2 affected individuals that were absent from 5 normal individuals. Direct sequencing was performed on SSCP positive patients.

PatientID: 3

KindredID: 3

Case: M, 47Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had a hemangioblastoma in the brainstem (cerebellopontine angle) and had high-normal Hb level (18.3).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

LegacyVariant: p.R161* (c.694C>T)

CaseProblemVariantFreeText: N/A

ClinVarID:2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: CA020408 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.481C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Of 38 PPGL (pheochromocytoma and paraganglioma) cases studied, one was associated with an individual carrying the germline mutation c.350G>C (ENSP00000256474.2 p.Trp117Ser) of the VHL gene. This mutation was identified using germline clinical sequencing on formalin-fixed and paraffin-embedded (FFPE) tissue and confirmed with sanger sequencing. The authors identified the reference sequence used as NM_000551.3. The patient (ID: RNSH08) presented with right adrenal phechromocytoma (31yo). No family history was clear or presented. This patient was previously published in PMID: 25545346.

PatientID: 94

KindredID: 94

Case: Sex Unknown, 27Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Carbonic anhydrase 9 (CA9) mRNA level of 26.95 was detected. Membrane CA9 immunostaining was observed.

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.Y156H (c.466T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756040

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y156H (c.466T>C)

MultipleGeneVariants: N/A

PatientID: 85

KindredID: 85

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history of VHL but no details provided.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1. There is additional tumour specific information in Supplemental Table 2.

Variant: p.P138P (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: Functionally validated by mRNA analysis, which showed a splicing alteration (data not shown). Membrane CA9 immunostaining was observed (supplemental table 1).

MutationType: missense_variant;transition; synonymous_variant

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

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This insertion mutation was detected in a VHL type 1 patient (family ID 4410), using PCR and SSCP sequencing. The mutation of c.386_387insAGA was referred to in the paper by c.599insAGA due to a difference in transcript sequence. The patient had retinal hemangioblastomas, CNS hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4).

GroupID: 512

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with germline variants c.227T>A and c.228C>T occuring in cis in the VHL gene. Member 11876 presented with moderate renal disease (RCC) and member 13998 had unknown renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.F76* (c.227_228delinsAA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320343, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_228delinsAA

gnomAD: N/A

VariantEvidence: Variants c.227T>A and c.228C>A occurred in cis, resulting in an amino acid change of p.Phe76Ter. This was mapped to c.227_228delinsAA.

MutationType: missense_variant;transversion; stop_gained

CivicName: F76* (c.227_228delinsAA)

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.F76* (c.227_228delinsAA) germline variant of the VHL gene was detected in a family (ID 512). Member 11876 presented with moderate renal disease (RCC) and member 13998 had unknown renal involvement. Variants c.227T>A and c.228C>A occurred in cis, resulting in an amino acid change of p.Phe76Ter.

GroupID: 3

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to harbor the c.468T>G germline variant of the VHL gene. Member 37 had no renal involvement. Member 38 presented with moderate renal disease (RCC). Members 47 and 3 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.Y156* (c.468T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756053, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.468T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y156* (c.468T>G)

MultipleGeneVariants: N/A

GroupID: 287

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family are reported as carrying the c.197_220del24 germline variant of the VHL gene. Member 6396 presented with mild renal disease. Member 6611 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 9829912, where 1 patient with this mutation is reported but relation to this patient is unclear.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.N67_V74del (c.197_221del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130203, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573130203

gnomAD: N/A

VariantEvidence: Variant reported as c.197_220del and was mapped to c.198_221del.

MutationType: inframe_deletion; deletion

CivicName: N67_V74del (c.197_221del)

MultipleGeneVariants: N/A

Case report of a 6Y girl presenting with pheochromocytoma was found with this de novo germline missense mutation in the VHL gene (c.268A>C), as the mutation was not present in either parent. Methods of sequencing were unclear. She was conceived by in vitro fertilization, therefore likely PS2. Patient's phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).

PatientID: V313

KindredID: V313

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1_340+5del

LegacyVariant: IVS1+1del5

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357098, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B1_340%2B5del

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; deletion; minus_2_frameshift_variant

CivicName: Splice Region (c.340+1_340+5del)

MultipleGeneVariants: N/A

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 L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA) mutation was found in 3 related individuals with VHL type 1 (no pheochromocytoma). Patient/proband no. V31. Three unaffected family members were not found to have the mutation.

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 V170G (c.509T>G) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V81). No unaffected family members were tested. This family was stated as being previously published in PMID 15300849 (no phenotypes specified).

PatientID: V81

KindredID: V81

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely 15300849

SupplementalData: N/A

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

Medical records of 26 patients diagnosed with VHL disease in two Korean hospitals between 2003-2012 and harboring germline VHL mutations were retrospectively reviewed. One male patient diagnosed with Type 1 VHL disease at 23Y (Patient 14) presented with renal cell carcinoma, multiple CNS hemangioblastomas and other manifestations. He had a germline inframe deletion in the VHL gene (c.227delTCT) and a negative family history of VHL disease.

PatientID: 20

KindredID: 13

Case: Sex Unknown, 24Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0030405; HP:0009711; HP:0000107; HP:0001737; HP:0010797 (pancreatic endocrine tumor, retinal capillary hemangioma, renal cyst, pancreatic cyst, hemangioblastoma)

CaseHPOFreeText: The patient at 24Y was confirmed with VHL. They developed PPGL at 24Y and also had the above manifestations

CaseNotHPOs: HP:0002668, HP:0002666; HP:0005584 (paraganglioma, pheochromocytoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V181Sfs*21 (c.541delG)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432423544 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.541delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V181fs (c.541delG)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: 11Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.446delC)

CaseProblemVariantFreeText: Paper reports this as a c.446delG mutation, however a C is positioned at c.446

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432421904 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.446del

gnomAD: N/A

VariantEvidence: paper mistake of "c.446 del G" should rather be 446 del C.

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.446delC)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 2

Case: Sex Unknown, 1Y0M, 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 0Y. Age at the end of study: 1Y.

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

A 49 year old female (Patient 3) from Europe presented with a unilateral adrenal pheochromocytoma. PCR-SSCP genetic testing on paraffin-embedded tissues and peripheral blood confirmed germline mutation in the VHL gene (p.214Gext14 (c.640T>G), referred to in the paper by p.X>Gly+14AA (c.852T>G) due to a difference in transcript sequence). Family history and patient demographic is unknown. This patient underwent surgical resection.

KindredID: 64

GroupID: 26

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 64 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 additional phenotypic information is listed for this kindred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N131Pfs*3 (c.390_391delTA)

LegacyVariant: p.201FS (c.603delTA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795179

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: N131fs (c.390_391del)

MultipleGeneVariants: N/A

GroupID/ KindredID: 26CA

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 26CA. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170F (c.508G>T)

LegacyVariant: p.V170F (c.721G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756193 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.508G>T

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transversion

CivicName: V170F (c.508G>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 (L101R (c.302T>G)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 23BMS. It was reported in the paper as c.515T>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: 51F

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 Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 51F. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P192Qfs*10 (c.575delC)

LegacyVariant: FS (c.786delC)

CaseProblemVariantFreeText: NM_000551.3:c.573delC automaps to c.575delC

ClinVarID: N/A

CAID: CA432423729 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.575delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P192fs (c.575delC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 2693NCI, 2956NCI, 20BMS, 2YO, 27BMS, 75CA, 48CA, 144CA

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 fromvarious families from multiple databases: including: the National Cancer Institute database, the Bristol Myers Squibb database,Department of Uroglogy, Yokohama database, and the Cambridge, Department of Pathology; with an unknown number of members belonging to each. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as 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: 7728151; 9829911

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

LegacyVariant: p.delF76 (c.439delTTC)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to updated NM_000551.3:c.227_229delTCT

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTCT)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3669NCI

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, with an unknown number of members belonging to Family ID 3669NCI. 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.S111Afs*48 (c.331delA)

LegacyVariant: FS (c.544delA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420649 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.331delA

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: S111fs (c.331delA)

MultipleGeneVariants: N/A

Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in a 42-year-old VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 12).

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The S168Tfs*2 (c.503_513del) germline mutation (reported as “c.716del11bp” according to legacy reference sequence) was found in a VHL type 1 family of 3. All three family members had renal cell carcinoma, two had hemangioblastomas of the central nervous system, and one had pancreatic cysts or tumors (unspecified) (family ID 63).

PatientID: 1 (case)

KindredID: 1

Case: F, 17Y0M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: Her father had bilateral pheochromocytoma at the age of 13 and her grandfather had died of an unknown renal disease at the age of 50. They were both however not tested for any variants. There were no reports of hereditary cutaneous or uterine leiomyomas, renal cell cancer, neuroendocrine tumors or hemangioblastomas of the CNS/retina. Further family evaluation revealed clinical and biochemical evidence of (bilateral) pheochromocytoma in two siblings 19 and age 23. These members also had the VHL mutation, while 2 unaffected family members were negative.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: She had persistent episodes of high blood pressure, and was imaging led to the detection of bilateral pheochromocytoma, and underwent an adrenalectomy (which was complicated by cardiac decompensation in the context of catecholamine-induced cardiomyopathy).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: FH/RET/MAX/NF1/SDHB/SDHC/SDHD/TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114G (c.342T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421783 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.342T%3EC

gnomAD: N/A

VariantEvidence: The FH variant is reported in 9/116704 alleles in the ExAC database. The VHL variant was no reported, however, an T>A transition at the same nucleotide position has been reported once in 1/121408 alleles (ExAC). Researchers suspect synonymous mutation has effects on transcript splicing (2 nucleotides into exon 2).

MutationType: synonymous_variant

CivicName: G114G (c.342T>C)

MultipleGeneVariants: Germline, FH, c.556-4A>G

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. 5 patients were found to have the above mutation (that causes the following protein change: E160Afs*12). 2 were VHL patients with ICTs (pancreatic neuroendocrine tumors) taken from the VHL-registry. The other 3 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: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease.

PatientID: 1

KindredID: 1

Case: F, 16Y0M, Ukrainian

DiseaseAssertion: Assumed VHL

FamilyInfo: Her brother (patient 2) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

CasePresentingHPOs: HP:0001901, HP:0005954, HP:0000077, HP:0001028 (polycythemia, pulmonary capillary hemangiomatosis, abnormality of the kidney, hemangioma )

CaseHPOFreeText: Patient had a hematocrit of 68%, erythropoietin level of 45 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo. She was diagnosed with polycythemia of unknown duration; at the age of 10 years, a pulmonary angioma was found and treated by a coil embolization. She continued to be polycythemic. At the age of 15 years, an abdominal computed tomography (CT) scan revealed a left renal mass, which on nephrectomy was determined to be a subcapsular hemangioma; there was no evidence of an angioma elsewhere. One year after surgery, she still remains polycythemic but has no evidence of a new or recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Y(c.376G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

gnomAD: N/A

VariantEvidence: Patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: D126Y(c.376G>T)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The L184R (c.551T>G) germline missense mutation of the VHL gene was found in a 44 yr old VHL patient with clear cell renal cell carcinoma as well as central nervous system and retinal hemangioblastomas (index case 363).

PatientID: IV-2

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: The transition mutation was found and confirmed in this patient, his great-aunt, and his first-cousin once removed. 5 additional members had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation. His mother, two uncles, and grandfather are all individuals with hemangioblastomas who have passed away.

CasePresentingHPOs: N/A

CaseHPOFreeText: Stated as carrier, however he is young (likely before the age of onset)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G)

LegacyVariant: p.L116V (c.559C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: II:1 (proband)

KindredID: 1

Case: M, 42Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband presented with VHL Type 2B. Sister presented with features of VHL Type 2A including cerebral hemangioblastomas, a right adrenal nodule, multiple cysts in the pancreas, multiple cysts in the liver, two brain lesions. The younger brother and their deceased father had hemangioblastomas in the central nervous system and ocular diseases, respectively. Despite having no information of detailed clinical data, it is reasonable to assume that they had VHL diseases. The father was also blind, but the reasons are unknown. The mother had no history of disease. Pedigree: see Figure 3.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0006770; HP:0030421 (Hemangioblastoma, Renal cell carcinoma, Clear cell renal cell carcinoma, Epididymal neoplasm)

CaseHPOFreeText: Ten years prior (at the age of 32), the patient received gamma knife treatment for cerebral hemangioblastomas. Magnetic resonance (MR) of the abdomen showed multiple solid lesions in the bilateral kidneys, multilocular renal cysts, a right adrenal nodule, multiple cysts and a solid lesion in the pancreas, and multiple cysts in the liver. The pathological manifestations confirmed ccRCC concurrent with simple renal cysts. The left side kidney showed multilocular cysts lined by clear cells. Pathology confirmed the presence of clusters of clear cells. mcRCC was confirmed pathologically. Scrotum MR suspected a malignant tumor on the right side epididymis.

CaseNotHPOs: HP:0000822; HP:0100631 (Hypertension, Neoplasm of the adrenal gland)

CaseNotHPOFreeText: No history of hypertension disease. Common tumor markers such as AFP, CEA, and PSA were normal. Special tests for adrenal lesions included plasma cortisol, renin angiotensin aldosterone, and urinary VMA, which were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA020288, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA020288

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

VariantEvidence: Direct sequencing of DNA strands revealed 2 recurrent mutations of c.256C > T (p.P86S) and c.340 + 5G > C. Haplotype construction displayed that the c.256C > T (p.P86S) mutation in cis with c.340 + 5G > C were located on the disease haplotype. Bioinformatics analysis revealed that this mutation might severely destabilize the hydrophobic core of pVHL and cause VHL manifestations. This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: P86S (c.256C>T) and Splice Region (c.340+5G>C)

MultipleGeneVariants: Germline, VHL, c.256C>T (p.Pro86Ser)

PatientID: 3 (proband)

KindredID: 2

Case: F, 56Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The same point mutation of VHL (c. 232A>T; p.Asn78Tyr) was identified in three family members including one sister, one brother and one nephew. Her sister was found with pancreatic NET and died of the hemorrhagic stroke at age of 40 years, and her brother and nephew refused for further examinations for VHL-related lesions. Her mother died of stroke at early of 50 years.

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

CaseHPOFreeText: at age 50, MRI scans revealed at least 3 lesions on her left kidney (recorded as bilateral RCC in August of 2011), and 3 lesions in her pancreas, which were stated to be pancreatic NETs.

CaseNotHPOs: HP:0006748, HP:0010797 (adrenal pheochromocytoma, cerebellar hemangioblastoma)

CaseNotHPOFreeText: MRI scan on brain was negative.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78Y (c.232A>T)

LegacyVariant: N/A

ClinVar: 223167 https://www.ncbi.nlm.nih.gov/clinvar/variation/223167/

CAID: CA357056 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.232A%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78Y (c.232A>T)

MultipleGeneVariants: N/A

PatientID: None (I)

KindredID: 7

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0030424 (epididymal cyst)

CaseHPOFreeText: Originally thought to be asymptomatic pre-testing; found epididymal cyst at first screening

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

KindredID: 11

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This is a family belonging to prefigure No. 11. They are described as ‘VHL-affected’.

GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152Hfs*22 (c.452_453insA)

LegacyVariant: p.222fs (c.665insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131771 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131771

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: T152fs (c.452_453insA)

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. RT-PCR analysis in RCC cell lines found a p.D143Tfs*29 (c.426_430del) mutation, stated in the paper as c.639_642del4 due to an older transcript. It was seen in cell line A-498. Any family information or other manifestations apart from RCC were unclear.

PatientID: 136

KindredID: 51

Case: M, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 136) has a mother (patient 137) who presented with a CNS hemangioblastoma at 32, and renal cell carcinoma/ pheochromocytoma at 38. However, no DNA sample was available for his mother's genetic testing.

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

CaseHPOFreeText: The proband (patient 136) presented with multiple pancreatic cysts/tumors at 21, renal cell carcinoma at 23, and a CNS hemangioblastoma at 25.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.P146Gfs*14 (c.435_436ins)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131810, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131810

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: P146Gfs*14 (c.435_436insGG)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A female patient (patient #41) was confirmed for germline mutation in the VHL gene (c.239del; p.Ser80Ilefs*79). She was diagnosed with renal cell carcinoma at 44Y and multiple pancreatic cysts or tumours at 44Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

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

Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). The mutation A122I (c.364_365GC>AT) was detected in the patient, referred to in the paper by c.577_578GC>AT due to a difference in transcript sequence. This missense mutation was found in the VHL gene and one patient with pheochromocytoma.

Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). The S68W (c.203C>G) mutation was detected in the patient, referred to in the paper by c.416C>G due to a difference in transcript sequence. This missense mutation was found in the VHL gene and one patient with pheochromocytoma.

PatientID: III-2

KindredID: 1

Case: M, 62Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: His mother (II,2) did not carry the mutation. His father (II-1) died age 42 from a cerebellar hemangioblastoma, while his paternal grandparents died at an advanced age and had no known history of VHL manifestations. His brother (III,1) did not harbour the mutation. The patient and his wife (III,3) who did not carry the mutation, had 3 daughters; two with the mutation and one without. Two of his daughters who carried the mutation, aged 28 and 36 (IV-2, IV-3), had a personal history of CNS and retinal hemangioblastomas. Patient IV-2 recently developed a ccRCC and a pheochromocytoma, and patient IV-3 a pancreatic neuroendocrine tumor. Refer to pedigree in Figure 1.

CasePresentingHPOs: HP:0006770, HP:0010797, HP:0009711 (clear cell renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma)

CaseHPOFreeText: The patient died at age 62 of CNS complications.

CaseNotHPOs: HP:0002666, HP:0030405 (pheochromocytoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: No erythrocytosis; the hematocrit, red blood cells count and Epo levels were all normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes supplemental data and figures. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Data.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Figures.pdf

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232 https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

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

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

VariantEvidence: The patient was a heterozygous carrier of a single R200W and R161Q mutation (both on the same VHL allele).

MutationType: missense_variant;transition

CivicName:R200W(c.598C>T) and R161Q(c.482G>A)

MultipleGeneVariants: Germline, VHL, c.482G>A (p.Arg161Gln)

GroupID: 32

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Unknown. One registrant from France has this mutation of c.525C>G

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175* (c.525C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182974 https://www.ncbi.nlm.nih.gov/clinvar/variation/182974/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y175* (c.525C>G)

MultipleGeneVariants: N/A

GroupID: 31

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Unknown. One registrant from France has this mutation of c.500C>A

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175* (c.525C>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351756231 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.525C%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y175* (c.525C>A)

MultipleGeneVariants: N/A

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.236_241delGCAGTC), which was found in 1 individual from Germany.


PatientID: 13

KindredID: 13

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0010797 (Renal neoplasm,Multiple renal cysts, Hemangioblastoma)

CaseHPOFreeText: Patient 13 was a 48-year-old male with a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, CNS hemangioblastoma.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.699C>G

CaseProblemVariant Free Text: N/A

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

CAID: CA357016

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transversion

CivicName: C162W(c.486C>G)

MultipleGeneVariants: N/A

Germline mutations were found in 20 Brazilian, VHL probands and their families. The L101R (c.302T>G) germline missense mutation was found in 2 affected family members with hemangioblastomas of the central nervous system (VHL family 5).

PatientID: 32

KindredID: 2301

Case: F, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of her family (patient 33) presented with one pathologic pancreatic neuroendocrine tumour and had the same VHL gene mutation.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with two pathologic pancreatic endocrine tumours with metastases.

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: 11

KindredID: 11

Case: F, 19Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0007850 (retinal vascular proliferation)

CaseHPOFreeText: Retinal vascular proliferation in the patient's eye were associated with a large fibrovascular component and was managed surgically. Presurgical and postsurgical optical coherence tomography in patient 11 demonstrated the fibrovascular complex as a hyperreflective layer that was limited to the vitreoretinal surface. There was traction on the underlying retinal tissue, resulting in thickening and obliteration of the foveal contour. Postsurgically, excision of the complex restored the overall shape of the foveal contour, leaving behind only a small disruption in the outer retinal lamination (corresponding perhaps to the inner segments at the base of the foveal pit) and a small residual macular epiretinal membrane.

CaseNotHPOs: HP:0002011, HP:0001732, HP:0012210 (Morphological central nervous system abnormality, abnormality of the pancreas, abnormal renal morphology)

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: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation. It was found in a VHL type 1 family of 5 individuals. Four family members had retinal angiomas and 3 had hemangioblastomas of the cerebellum.

GroupID: 31

DiseaseAssertion: assumed VHL

GroupSize: 30

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 30 of the 573 patients discussed in this paper were found to have identical variants. This nonsense mutation (R161* (c.481C>T)) was found in 7 VHL families with 30 patients altogether.

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

GroupHPOFreeText: 24 had retinal hemangioblastoma, 13 had cerebellar hemangioblastomas, 14 had renal cell carcinoma, and 3 had pheochromcytoma. Mean ages for each diagnosis follows: 23 (RH), 28 (CHB), 38.7 (RCC), 34 (Pheo)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 48

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 S1 describes 19 patients with missense mutations, including this patient.

Variant: p.Q164L (c.491A>T)

LegacyVariant: c.704A>T

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756149

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Q164L (c.491A>T)

MultipleGeneVariants: N/A

PatientID: 60

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 S1 describes 19 patients with missense mutations, including this patient.

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

LegacyVariant: c.701T>A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756137

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L163H(c.488T>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 147

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 147

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121Mfs*38 (c.361delG)

CaseProblemVariantFreeText: N/A

LegacyVariant: FS (c.574delG)

ClinVarID: N/A

CAID: CA432421803 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: D121Mfs*38 (c.361delG)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: None - The family history was negative for hypertension, PHEO or other neuroendocrine tumours. Their parents however, decided not to be tested neither to extend the test to other family members

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Apparently sporadic pheo. He had a history of occipital headache, slightly elevated blood pressure with normal ophthalmological examination for 2 months was found to have a 4-cm-diameter left adrenal mass at MRI, being the abdominal sonography negative. He underwent surgery of the pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D197N (c.589G>A)

LegacyVariant: p.D197N (g.13,278)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756524 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.589G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D197N (c.589G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A - Not specified

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: VHL syndromic HB (both germline and somatic variants were observed

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R120_121S (c.360_362delAGA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131861 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131861

gnomAD: N/A

VariantEvidence: A VHL subject in our patient population had a full length deletion (FLD) in the germline VHL gene, but a VHL gene tumor second hit mutation (c.360_362delAGA) causing an amino acid change of p.R120-121S detected in the HB tumor

MutationType: delins

CivicName: Deletion AND R120_121S (c.360_362delAGA)

MultipleGeneVariants: Germline, VHL, complete deletion

A cohort of 314 patients with pheochromocytoma and functional paraganglioma had blood samples collected and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened for mutations. 25 patients had germline VHL mutations, 16 of which had a family history and 9 patients had an apparently sporadic presentation, 11 were male and 14 were female, the median age of diagnosis is 23.9 and range of diagnosis was 4-49. Out of the 25 patients 23 had adrenal tumours, 4 had para-adrenal tumours, and 9 had other VHL lesions (renal tumours and hemangioblastomas). 2 patients with postive family history and/or a syndromic presentation were found with pheochromocytoma or functional paraganglioma and a germline missense VHL mutation (c.290C>T). Other phenotypes unique to the patient are unknown. ACMG: PP4

PatientID: None

KindredID: 1

Case: F, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Positive. Patient's mother did not undergo genetic testing but had a hemangioblastoma at age 50 and a pancreatic cyst or tumour at age 62. The patient's sister (the proband) also had this mutation and presented with hemangioblastoma (age 35), retinal angioma (age 37), pancreatic cysts or tumours (age 37), and renal cell carcinoma (age 39). Another one of the patient's sisters presented with hemangioblastoma (age 40), renal cell carcinoma (age 43), and pancreatic cysts or tumours (age 43). This patient died before diagnosis. The proband's brother also died before diagnosis and presented with hemangioblastoma and retinal angioma at age 27.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0009715, HP:0010797, HP:0005584, HP:0001732, HP:000971(pheochromocytoma, Papillary cystadenoma of the epididymis, hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

SupplementalData: N/A

Variant: p.Y98N (c.292T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351750883 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y98N (c.292T>A)

MultipleGeneVariants: N/A

PatientID: IV-6

KindredID: 1

Case: F, 38Y0M, Chinese

DiseaseAssertion: Glioblastoma

FamilyInfo: Eight affected individuals in the patient’s family were retrospectively identified by reviewing medical records and from the recall of relatives. Three had passed away before 40 years of age because of central nervous system hemangioblastoma. Among the 10 living family members that carried the same NM_000551.3:c.326_339dupTCCACAGCTACCGA the patient carried, 3 had renal cysts and 1 had developed renal cell carcinoma, 2 had central nervous system hemangioblastoma, 1 had retinal hemangioblastomas, 1 was diagnosed with glioblastoma, and 5 were asymptomatic.

CasePresentingHPOs: ORPHA:360 (Glioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584 (Retinal hemangioblastoma, hemangioblastoma, renal cyst, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Gly114Serfs*50(c.326_339dupTCCACAGCTACCGA)

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2573051018 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051018

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: G114fs (c.326_339dupTCCACAGCTACCGA)

MultipleGeneVariants: N/A

GroupID: 33

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

GroupPresentingHPOs: N/A

GroupHPOFreeText: These 2 patients with a c.388G>A mutation did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: V130I (c.388G>A)

MultipleGeneVariants: N/A

PatientID: 23

KindredID: 23

Case: F, 45Y0M, 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: p.F76del (c.224_226delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 45Y0M, Japanese

DiseaseAssertion: VHL

FamilyInfo: No evidence of a family history of VHL.

CasePresentingHPOs: HP:0001737; HP:0030405; HP:0006880; HP:0006748; HP:0009711; HP:0001732; HP:0002896 (Pancreatic cysts, Pancreatic endocrine tumor, Cerebellar hemangioblastoma, Adrenal pheochromocytoma, Retinal capillary hemangioma, Abnormality of the pancreas, Neoplasm of the liver)

CaseHPOFreeText: The proband had a cerebellar hemangioblastoma resected at age 17, retinal hemangioblastoma surgery at age 26, and an adrenalectomy for pheochromocytoma at age 30. An abdominal CT revealed a 4cm abdominal mass and diffuse pancreatic cystic lesions, diagnosed as pancreatic neuroendocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText:

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q132* (c.394C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA10606205 (http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA10606205)

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q132* (c.394C>T)

MultipleGeneVariants: N/A

All patients included in the study were VHL mutation carriers of 18 years or older examined between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU). Clinical data of 75 VHL mutation carriers were retrospectively retrieved from electronic and written patient record. Of these patients, one was found to harbour the c.89_297del germline mutation of the VHL gene. They presented with a retinal hemangioblastoma, cerebellar hemangioblastoma, spinal hemangioblastoma, renal cell carcinoma, pancreatic endocrine tumor, renal cyst and pancreatic cysts. Their age at the last follow-up was 70. They were previously published in PMID 24132471.

PatientID: N/A (brother of index case)

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's sister was the index case in this VHL family, as she was diagnosed with bilateral pheochromocytoma at age 23 and underwent bilateral adrenalectomy. Genetic screening revealed the VHL variant, which prompted screening of family members. DNA sequencing from blood of consenting family members confirmed the presence of the VHL variant in seven family members (three generations) (see figure 1 for familial pedigree). This included the sister (index case), two nephews, mother, and two daughters. The patient's two daughters both had the mutation. One of which was found to have pheochromocytoma at age 15 due to routine screening. The other 8 year old daughter has not had any manifestations. The patient’s nephew was asymptomatic until age 7, where an abdominal ultrasound revealed a left adrenal mass. A total adrenalectomy was performed and at age 1 another mouse was found in the right adrenal gland, which was also removed. 6 years later he was asymptomatic. The patient’s other nephew presented with an adrenal mass at 11Y0M, which required total adrenalectomy and remains well 2.5 years later. No phenotype was noted for the patient’s mother.

CasePresentingHPOs: HP:0006748;HP:0010797; HP:0005584 (adrenal pheochromocytoma; Hemangioblastoma; Renal cell carcinoma)

CaseHPOFreeText: Patient developed hemangioblastoma, multiple bilateral renal cell carcinomas, bilateral pheochromocytomas, and succumbed to his disease at age 45.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; tranversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

PatientID: V5

KindredID: 3

Case: M, 47Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Sister presented with the same germline mutation and at least one cerebellar hemangioblastoma at the age of 29.

CasePresentingHPOs: HP:0006880(Cerebellar hemangioblastoma)

CaseHPOFreeText: Presented with at least two brainstem hemangioblastoma at the age of 35 and and 47.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H110P (c.329A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751310, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351751310

gnomAD: N/A

VariantEvidence: The c.329A>C variant was not genetically confirmed to be germline but was found in samples from both tumors presented by this patient.

MutationType: missense_variant;transversion

CivicName: H110P (c.329A>C)

MultipleGeneVariants: N/A