PatientID: 7

KindredID: 7

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0010797; HP:0001737; HP:0006770 (Renal neoplasm, Multiple renal cysts, Hemangioblastoma, Pancreatic cysts, Clear cell renal cell carcinoma)

CaseHPOFreeText: Patient 7 had a medical history of a left solid renal tumor and multiple renal cysts. They also had central nervous system hemangioblastomas and pancreatic cysts.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.447del)

LegacyVariant: c.661delA

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: CA432421904, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.447del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.447del)

MultipleGeneVariants: N/A

PatientID: 58

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.E160Afs*13(c.479_480delAG)

LegacyVariant: c.691_692delAG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621940

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant; deletion

CivicName: E160FS(c.479_480delAG)

MultipleGeneVariants: N/A

PatientID: 18

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S5 describes 8 patients with frameshift or in-frame deletions, including this patient.

Variant: p.F76del(c.224_226del)

LegacyVariant: c.437_439delTCT

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: F76del(c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 26

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 S6 describes 3 patients with small insertions, including this patient.

Variant: p.R69Afs*63 (c.204dup)

LegacyVariant: c.417insG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant, duplication

CivicName: R69Afs*63 (c.204_205insG)

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M, Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797 (retinal capillary hemangioma; pheochromocytoma; hemangioblatoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: 9

KindredID: A

Case: F, Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. The father and one uncle were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: HindIII and revealed an aberrant banding pattern in three affected family members (1, 2, and 9)

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: 2

KindredID: A

Case: M, Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient’s last two brothers were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID:N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: HindIII and revealed an aberrant banding pattern in three affected family members (1, 2, and 9)

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: 1

KindredID: A

Case: F, Age unknown, Turkish

DiseaseAssertion: VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. The proband’s last two brothers were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma; hemangioblastoma; renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID:N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: HindIII and revealed an aberrant banding pattern in three affected family members (1, 2, and 9); Southern blot analysis after EcoR1 digestion, with the g7 probe and an internal control probe, demonstrated an extra band above the 20-kb normal fragment

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: III1(Ca001)

KindredID: C

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient’s grandfather (I-2) presented with hemangioblastoma and possessed the same exon 2 deletion. The patient’s mother also possessed the deletion and had hemangioblastoma. Mother’s sister (II-3) had retinoblastoma, pancreatic cyst and pheochromocytoma, while the mother’s other sibling (II-5) had hemangioblastoma, pancreatic cyst, and clear cell renal carcinoma. The patient’s 2 cousins each possessed the same deletion, but did not exhibit phenotypes (Please see Figure 1. Family C matches with Pedigree B).

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0006770; HP:0001737; HP:0002666; HP:0009919 (Hemangioblastoma; clear cell renal cell carcinoma; pancreatic cysts; pheochromocytoma, retinoblastoma)

CaseNotHPOFreeText: Patient did not present with any symptoms.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: large fragment deletion in exon 2

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as GRCh37 chr3:10188300ATATCACACTGCCA>T in paper

MutationType: minus_2_frameshift_variant; deletion

CivicName: Exon 2 (deletion)

MultipleGeneVariants: N/A

PatientID: II3(Cb01)

KindredID: C

Case: F, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s father (I-2) presented with hemangioblastoma and possessed the same exon 2 deletion. The patient’s two siblings also possessed the deletion. The sister (II-1) had hemangioblastoma, while the other sibling (II-5) had hemangioblastoma, pancreatic cyst, and clear cell renal carcinoma. The patient and her two siblings each had a child and all possessed the same deletion, but did not exhibit phenotypes (Please see Figure 1. Family C matches with Pedigree B).

CasePresentingHPOs: HP:0009919; HP:0002666; HP:0001737 (Retinoblastoma; Pheochromocytoma; Pancreatic cysts)

CaseHPOFreeText: Patient presented with Retinoblastoma, pheochromocytoma, and pancreatic cystic disease.

CaseNotHPOs: HP:0006770; HP:0010797 (Clear cell renal cell carcinoma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: large fragment deletion in exon 2

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as GRCh37 chr3:10188300ATATCACACTGCCA>T in paper

MutationType: minus_2_frameshift_variant; deletion

CivicName: Exon 2 (deletion)

MultipleGeneVariants: N/A

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Peripheral blood leukocytes were isolated and directly sequenced using the BigDye Terminator Cycle Sequencing Ready Reaction kit on an ABI Prism 3130 genetic analyzer (Applied Biosystems). One patient presented with the c.173insC germline variant of the VHL gene. Patient 1, 17Y female previously reported in PMID 19270817, presented with CNS hemangioblastoma and a family history positive for VHL.

PatientID: 55

KindredID: 55

Case: F, 44Y0M, Korean

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

PatientID: Daughter

KindredID: 1

Case: F, 35Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Father and brother presented with the same VHL mutation. Brother presented with a meningioma, pancreatic lesions and bilateral renal cysts all at 38Y. Father presented with cerebellar hemangioblastoma 49Y, retinal hemangioblastoma 64Y, bilateral renal cell carcinoma 51Y and multiple pancreatic neuroendocrine tumors 64Y.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0030405; HP:0000107 (Cerebellar hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst)

CaseHPOFreeText: Cerebellar hemangioblastoma, renal cell carcinoma, multiple pancreatic neuroendocrine tumors and bilateral renal cysts all at 35Y. Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.M54Gfs*77 (c.160_161del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189210, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.160_161del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_frameshift_variant

CivicName: M54Gfs*77 (c.160_161delAT)

MultipleGeneVariants: N/A

PatientID: None (X)

KindredID: 7

Case: Sex and Ethnicity unknown; Age <18Y0M

DiseaseAssertion: Asymptomatic

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

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

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

The genetic testing program for VHL disease included 17 families, ten of which had definite VHL disease and seven had possible VHL disease. 17 families (n=109 individuals) were tested for VHL mutations using peripheral blood. Mutation analysis was performed by direct sequencing of the VHL gene. Mutations were identified in 36 patients. Mutations-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. Tumor status and phenotypes were documented at initial screening and at follow ups. 6 (3 adults and 3 children) members from family 6 were tested positive with c.99_100InsA mutation. 2 adult and 1 pediatric patients were affected at initial screening. Another adult patient was affected by VHL disease at follow up. The other 2 children were asymptomatic both at initial screening and at last follow up. 13 (7 adults and 6 children) members from family 7 were tested positive with c.99_100InsA mutation. 9 members were affected by clinical VHL disease in total by the final follow up. The other 4 patients (whom were all pediatric) were asymptomatic at last follow up. ACMG evidence codes: 'PP4' because the patients' family history are highly specific for a disease with single genetic etiology.

PatientID: None (II)

KindredID: 7

Case: Sex and Ethnicity unknown; Age <18Y0M

DiseaseAssertion: Asymptomatic

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

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

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

PatientID: None (XIII)

KindredID: 7

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: asymptomatic

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

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

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

Medical records of 31 Asian Indian genetically proven VHL patients with pheochromocytoma/paraganglioma were studied. Two unrelated patients were genetically confirmed (PCR and Sanger sequencing) to have a germline frameshift mutation at c.224_226delTCT of the VHL gene. Patient 21 (M): presented with unilateral pheochromocytoma (29Y), pancreatic cysts (29Y), renal cell carcinoma (29Y) and a central nervous system hemangioblastoma (29Y). He has a negative family history. Patient 26 (F): presented with unilateral pheochromocytoma (45Y) and a negative family history.

GroupID: None

KindredID:9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed/Latino

GroupAgeRange: N/A

GroupInfo: Three members of a South American family expressed this c.344delA mutation.

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

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Pfs*44 (c.344delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70049370 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.344delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H115Pfs*44(c.344delA) and P61=(c.183C>G)

MultipleGeneVariants: Germline, VHL,c.c.183C>G (p.Pro61Pro)

Germline mutations were found in 20 Brazilian, VHL probands and their families. Peripheral blood samples were taken and genomic DNA was sequenced using PCR and Southern Blotting. The three exons of the VHL gene were amplified by PCR, sequenced in both strands with Big Dye terminators (Applied Biosystems), and collected and analysed on an ABI Prism 377 (Applied Biosystems). Germline rearrangements involving part or the entire VHL gene were detected by quantitative Southern blotting using g7 cDNA11 and a β globin probe. This mutation, H115Pfs*44 (c.344delA) , was found in a VHL type 1 family of 3 affected individuals (VHL family 9). This mutation caused a frameshift to occur leading to the protein terminating at residue 157. One had hemangioblastomas of the central nervous system, one with retinal angiomas, and one with renal carcinoma. Within this family a second mutation was also discovered in the VHL gene, P61= (183C>G), which was assumed to not be deleterious. ACMG codes as follows: A frameshift mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).

“None of the novel mutations were represented in 120 alleles from normal subjects in the Brazilian population suggesting that these base changes are not common polymorphisms.”

GroupID: None

KindredID: 17

DiseaseAssertion: VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed /Latino

GroupAgeRange: N/A

GroupInfo: 10 members of a South American family expressed this mutation.

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

GroupHPOFreeText: All 10 family members had a central nervous system hemangioblastoma. One also had a retinal angioma. Five had renal carcinoma. One patient per family with renal tumour <3 cm under follow up detected by imaging.

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: Deletion

CivicName: Partial Deletion and P61=( c.183C>G)

MultipleGeneVariants: Germline, VHL, c.183C>G (Pro61Pro)

GroupID: 5

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 2 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

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

GroupNotHPOs: HP:0002894; HP:0009711; HP:0002666; HP:0005584; HP:0009726 (Neoplasm of the pancreas, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma, Renal neoplasm)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

“None of the novel mutations were represented in 120 alleles from normal subjects in the Brazilian population suggesting that these base changes are not common polymorphisms.”

PatientID: None

KindredID: 97

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 97

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.W117* (c.351G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.W117* (c.564G>A)

ClinVarID: N/A

CAID: CA351753679 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.351G%3EA

gnomAD: 0.000003976 https://gnomad.broadinstitute.org/variant/3-10188208-G-A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W117* (c.351G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 144

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 144

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488; 17024664

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F76del (c.440delTCT)

ClinVarID: N/A

CAID: CA357012 http://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

PatientID: None

KindredID: 107

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 107

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.N141Mfs*18 (c.421delA)

CaseProblemVariantFreeText: NM_000551.3:c.421delA automapps to NM_000551.3:c.422delA

LegacyVariant: FS (c.634delA)

ClinVarID: N/A

CAID: CA432421876 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.421delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N141fs (c.422del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 134

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 134

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488, 17024664

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F76del (c.440delTCT)

ClinVarID: N/A

CAID: CA357012 http://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_229delTTC)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: Unknown, 36Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText:The patient presented with hemangioblastoma at age 35. One year later he was found to have renal cell carcinoma and pancreatic cysts or tumors.

CaseNotHPOs: HP:0009711, HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.V62Efs*68 (c.185_193delTGCTGCGCTinsAGCA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA2499306941 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306941

gnomAD:N/A

VariantEvidence: N/A

MutationType: delins

CivicName:V62Efs*68 (c.185_193delTGCTGCGCTinsAGCA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 8

Case: Unknown, 24Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText:The patient presented with hemangioblastoma at age 18. At age 24 the patient had renal cell carcinoma and cysts/tumours of the pancreas.

CaseNotHPOs: HP:0009711, HP:0002666(retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.W117S(c.350G>C)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117S(c.350G>C)

MultipleGeneVariants: N/A

Using polymerase chain reaction (PCR)-direct sequencing and universal primer quantitative fluorescent multiplex–PCR, mutations in VHL gene in 19 VHL disease families recruited from the Department of Urology, Peking University First Hospital in the period from 2009 to 2012 were examined. One proband (family 9) was found to carry the mutation c.343delC in exon 2 of the VHL gene. The proband presented with hemangioblastoma at age 26 and renal cell carcinoma and abnormality of the pancreas at age 36. The patient had negative VHL family history. This patient was previously published in 29330336.

PatientID: None

KindredID: 16

Case: F, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's sibling was the proband and presented with hemangioblastoma, renal cell carcinoma, and abnormality of the pancreas. Her niece also had the mutation but was asymptomatic. Another member of her family also had this mutation and was asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797, HP:0009711, HP:0002666, HP:0005584, HP:0001732 (hemangioblastoma, retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: M, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's uncle was the proband and presented with hemangioblastoma, renal cell carcinoma, and abnormality of the pancreas. The patient's mother and cousin also had the mutation but were asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797, HP:0009711, HP:0002666, HP:0005584, HP:0001732 (hemangioblastoma, retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 41F

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 41F. 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.Y156* (c.468T>G)

LegacyVariant: p.Y156* (c.681T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

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

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 41CA

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 41CA. 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.L153Cfs*6 (c.457delC)

LegacyVariant: FS (c.670delC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421920 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.457delC

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: L153fs (c.457delC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3759NCI, 3760NCI

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 IDs 3759NCI and 3760NCI. 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: 7728151

SupplementalData: N/A

Variant: p.Y112* (c.336C>A)

LegacyVariant: p.Y112* (c.549C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16602183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.336C>A

gnomAD: N/A

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

MutationType: stop_gained

CivicName: Y112* (c.336C>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 147CA

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 Family 147CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as a VHL family without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: FS (c.574delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

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: D121fs (c.361delG)

MultipleGeneVariants: N/A

GroupID/ KindredID: 40CA

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 40CA. 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.G114C (c.340G>T)

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

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G114C (c.340G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 146CA

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 Family 146CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A56Sfs*76 (c.165_166insA)

LegacyVariant: FS (c.378insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524648 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.165_166insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: A56fs (c.165_166insA)

MultipleGeneVariants: N/A

GroupID/ KindredID: 71CA

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 71CA. 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.C77Lfs*55 (c.228_229insC)

LegacyVariant: FS (c.441insC)

CaseProblemVariantFreeText: NM_000551.3:c.228_229insC automaps to c.228dupC

ClinVarID: N/A

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

gnomAD: N/A

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

MutationType: plus_1_frameshift_variant; duplication

CivicName: C77fs (c.228dupC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 4BMS. 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: (c.464-2A>C)

LegacyVariant: Splice (c.677-2A>C)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756024 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.464-2A>C

gnomAD: N/A

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 141CA

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 141CA. 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.L188Rfs*14 (c.563delT)

LegacyVariant: FS (c.776delT)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423679 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.563delT

gnomAD: N/A

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

MutationType: minus_1_frameshift_variant

CivicName: L188fs (c.563delT)

MultipleGeneVariants: N/A

GroupID/ KindredID: 11BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 11BMS. 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.T152Hfs*22 (c.452_453insA)

LegacyVariant: FS (c.665insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131771 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.452_453insA

gnomAD: N/A

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

MutationType: plus_1_frameshift_variant

CivicName: T152fs (c.452_453insA)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 3

Case: F, 53Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: Sister was thought to be sporadic (non familial) in 2001 with a spinal T7 tumor - genetic testing in this paper describes her (the sister, case 3) without any mutations.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53. She had a germline point and 2 somatic point mutations found in the DNA of her CHB. These mutations are discussed further in PMID: 24335534

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24335534 (pt. HGB-25)

SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

Variant: p.D126Rfs*6 (c.375_376insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320316 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320316

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P25L(c.74C>T) and D126Rfs*6(c.375_376insA) and E55Rfs(c.163delG)

MultipleGeneVariants: Somatic, VHL, c.163delG (p.Glu55Argfs), Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: 27

KindredID: 9

Case: F, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband, patient 27, presented at age 36 with a CNS hemangioblastoma, and renal cell carcinoma and multiple pancreatic cysts and tumors at 40.

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). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

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

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 98

KindredID: 33

Case: M, 43Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 97) presented with a CNS hemangioblastoma at 37, retinal angioma at 20, and renal cell carcinoma and multiple pancreatic cysts/tumors at age 29. Their brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseHPOFreeText: The proband's brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

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: p.P97Afs*35 (c.287_288insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420510, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.287_288insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P97Afs*35 (c.287_288insA)

MultipleGeneVariants: N/A

PatientID: 157

KindredID: 58

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 155) has a sister (patient 156) and a nephew (son of sister, patient 157) that were both genetically confirmed with the mutation. The sister presented with a CNS hemangioblastoma at 21 and multiple pancreatic cysts/tumors at 27, and the nephew was asymptomatic at the time of analysis.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's nephew (son of sister) was asymptomatic at the time of analysis.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, 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.E160Dfs*10 (c.480del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423139; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA432423139

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.480delG)

MultipleGeneVariants: N/A

PatientID: 153

KindredID: 56

Case: F, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a retinal angioma at 26, and multiple pancreatic cysts/tumors at 31.

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

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.I151N (c.452T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754356; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA351754356

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: I151N (c.452T>A)

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. This familial mutation was confirmed in family #50. Only the proband (patient 132) was genetically confirmed with the mutation. The proband (female) was diagnosed with a CNS hemangioblastoma at 26Y, renal cell carcinoma at 45Y, and multiple pancreatic cysts/tumors at 45Y. Her father (patient 135) was diagnosed with CNS hemangioblastoma at 25Y, but passed away before VHL disease diagnosis/ mutation confirmation. Her first brother (patient 133) was diagnosed with CNS hemangioblastoma at 29Y, RCC at 48Y, and multiple pancreatic cysts/tumors at 48Y, but no DNA sample was available for testing. Her second brother (patient 134) was diagnosed with CNS hemangioblastoma at 27Y, but passed away before VHL disease diagnosis/ mutation confirmation. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 122

KindredID: 43

Case: F, Age 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 19, and multiple pancreatic cysts/tumors at 26.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

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. This familial mutation was confirmed in family #43 with 2 affected members that were both genetically confirmed for the mutation. A female proband was diagnosed with CNS hemangioblastoma at 19Y and multiple pancreatic lesions at 26Y. Her father was diagnosed with CNS hemangioblastoma at 27Y, renal cell carcinoma at 48Y, and multiple pancreatic lesions at 60Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336). It is likely that both papers published the same family.

PatientID: 155

KindredID: 58

Case: M, 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 155) has a sister (patient 156) and a nephew (son of sister, patient 157) that were both genetically confirmed with the mutation. The sister presented with a CNS hemangioblastoma at 21 and multiple pancreatic cysts/tumors at 27, and the nephew was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband presented at age 21 with retinal angioma, and at age 26 with multiple pancreatic cysts/tumors and renal cell carcinoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.E160Dfs*10 (c.480del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423139; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA432423139

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.480delG)

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. This familial mutation (p.P97Afs*35, c.287_288insA) was confirmed in family #33, with 2 affected members that were both genetically confirmed for the mutation. A male proband (patient 99) was diagnosed with CNS hemangioblastoma at 37Y, retinal angioma at 20Y, renal cell carcinoma at 20Y, and multiple pancreatic cysts or tumours at 29Y. His brother (patient 100) was diagnosed with retinal angioma at 32Y, renal cell carcinoma at 43Y, and multiple pancreatic cysts or tumours at 43Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #48. Only the male proband (patient 128) was genetically confirmed with the mutation. He was diagnosed with CNS hemangioblastoma at 32Y, RCC at 38Y, pheochromocytoma at 40Y and multiple pancreatic lesions at 38Y. His father (patient 129) was diagnosed with RCC at 58Y and his daughter (patient 130) was diagnosed with CNS hemangioblastoma at 13Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 124

KindredID: 44

Case: M, Age 24Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 18, renal cell carcinoma and multiple pancreatic cysts/tumors at 24.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID: 24581539) and 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.W117S (c.350G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117S (c.350G>C)

MultipleGeneVariants: N/A

PatientID: IP (Proband)

KindredID: C

Case: M, 35Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Index patient presented with cerebellar hemangioblastoma, renal cysts, pancreatic cyst and bilateral renal cell carcinomas. Family members were not available for clinical and genetic screening except a brother whose screening revealed no abnormality.

CasePresentingHPOs: HP:0006880; HP:0005562; HP:0005584; HP:0001737 (Cerebellar hemangioblastoma, Multiple renal cysts, Renal cell carcinoma, Pancreatic cysts)

CaseHPOFreeText: Patient was operated for cerebellar hemangioblastoma at the age of 33 years. Preoperative clinical screening also showed renal cysts. Two years later, a pancreatic cyst and bilateral renal cell carcinomas were found and the patients underwent bilateral nephrectomy with subsequent chronic hemodialysis. Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Heterozygous deletion of Exon 3.

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: III-5

KindredID: Family A

Case: F, 32Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s grandfather (I-1), now deceased, and aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. Her mom II-2 had confirmed VHL and CNS hemangioblastoma; and her cousin (III-6) has renal cell carcinoma and CNS/spinal hemangioblastoma and also the confirmed VHL gene mutation. Her uncle (II-3) has confirmed VHL gene and pancreatic and renal cysts. Her brother and sister (III-3; III-4) both were found with the confirmed VHL gene mutation; III-3 with retinal hemangioblastoma and CNS/spinal hemangioblastomas and III-4 with pancreatic and ovarian cysts. IV-1 and IV-3, were confirmed with the VHL gene mutation although no other manifestations.

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

CaseHPOFreeText: developed hemangioblastoma at the optic nerve in her left eye at the age of 16. At the age of 30, patient A III-5 underwent surgery for a CNS hemangioblastoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 3 (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

GroupID: 19

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0001737 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Pancreatic cysts (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

GroupID: 15

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0001737; HP:0030424 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts, Epididymal cyst)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

GroupID: 43

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0030393; HP:0001737; HP:0030405 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Pancreatic endocrine tumor)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (2), Retinal capillary hemangioma (4), Hemangioblastoma/brain/cerebellum (3), Endolymphatic sac tumor (2), Pancreatic cysts (3), Pancreatic endocrine tumor (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, IRAK2, partial deletion

MultipleGeneVariants: Germline, ENST197804, partial deletion

GroupID: 49

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0000107; HP:0010797; HP:0009713; HP:0001737 (Renal cyst, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cyst (1), Hemangioblastoma/brain/cerebellum (4), Spinal hemangioblastoma (3), Pancreatic cysts (2)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, FANCD2, partial deletion

MultipleGeneVariants: Germline, IRAK2, deletion

GroupID: 24

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: Germline, IRAK2, partial deletion

GroupID: 36

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

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

GroupHPOFreeText: # of affected individuals: Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

GroupID: 2

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0009711; HP:0009713; HP:0030393; HP:0030424 (Retinal capillary hemangioma, Spinal hemangioblastoma, Endolymphatic sac tumor, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Retinal capillary hemangioma (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, ENST197804, partial deletion

GroupID: 7

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0002666; HP:0009711; HP:0010797; HP:0009713; HP:0001737 (Renal cell carcinoma, Renal cyst, Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

GroupID: 5

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 of the 573 patients discussed in this paper were found to the mutation belonging to 1 family. This mutation (c.176delC) was found in 1 VHL family with 5 patients.

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

GroupHPOFreeText: 3 patients had retinal angiomas diagnosed at a mean age of 22Y, 4 patients had cerebellar hemangioblastomas diagnosed at a mean age of 24Y, and 2 patients had RCCs with a mean age of diagnosis of 60Y.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.P59Rfs*8 (c.176delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432536374 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.176delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P59fs (c.176delC)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 of the 573 patients discussed in this paper were found to the mutation belonging to 1 family. This mutation (c.194delC) was found in 1 VHL family with 7 patients.

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

GroupHPOFreeText: 3 patients had retinal angiomas diagnosed at a mean age of 18Y, 2 patients had cerebellar hemangioblastomas diagnosed at a mean age of 33Y, and 2 patients had RCCs with a mean age of diagnosis of 30Y and one single patient had pheos diagnosed at age 20Y.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65Wfs*2 (c.194delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432536395 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S65FS (c.194delC)

MultipleGeneVariants: N/A

GroupID: 50

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family

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

GroupHPOFreeText: 4 patients had retinal angiomas diagnosed at a mean age of 27Y, and 3 had cerebellar hemangioblastomas diagnosed at a mean age of 32Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R82_V84del (c.243_251delGCGCGTCGT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658820713 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.243_251del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: R82_V84del (c.243_251del)

MultipleGeneVariants: N/A

GroupID: 4

Case: 24Y0M, 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.166dupG) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0009711; HP:0006880 (retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: patient had cerebellar hemangioblastoma at 15Y and retinal capillary hemangioma at 24Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.A56Gfs*76 (c.166dupG)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA645524645 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.166dupG

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: A56fs (c.166dup)

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

Through blood sample testing, ten affected individuals from 7 families in Singapore were identified with VHL disease. One patient of Chinese ethnicity was found with the c.393C>G (p.Asn131Lys) mutation in the VHL gene and presented with CNS hemangioblastoma, retinal angioma, renal cell carcinoma, renal cysts, and pancreatic cysts. ACMG: PP2, PP4

PatientID: 16 (Uncle)

KindredID: 18

Case: M, 68Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

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

CaseHPOFreeText: This patient presented with pheochromocytoma (23Y). Age of diagnosis for CNS hemangioblastoma and renal cell carcinoma is unknown.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

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

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 93 (First cousin once removed)

KindredID: 18

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: This patient presented with pheochromocytoma (31Y). Patient died at 31Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

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

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 6 (Mother)

KindredID: 18

Case: F, 75Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (54Y) and retinal angioma (28Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

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

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 128 (Second cousin)

KindredID: 18

Case: M, 52Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

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

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

CaseHPOFreeText: This patient presented with pheochromocytoma (11Y). Age of diagnosis for retinal angioma is unknown.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

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

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

GroupID/ KindredID: 5

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

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

GroupHPOFreeText: all 3 patients were tallied with retinal capillary hemangiomas and 2 with cHemangioblastomas. These phenotypes could be paired with the same or different members in this family as it was not clear.

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: None of the patients were recorded to have RCC

GroupPreviousTesting: N/A

PreviouslyPublished: 32179488

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

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

LegacyVariant: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

GroupID/ KindredID: 6

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This mutation was found in Family No. 6 with 1 member affected.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

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

LegacyVariant: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

GroupID/ KindredID: 24

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this deletion.

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

GroupHPOFreeText: Both (2) patients had hemangioblastomas, and RCC, and 1 had retinal capillary hemangioma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 deletion

CaseProblemVariantFreeText: Patients were both found with an Exon 3 deletion (and 8.5 kb abnormal band on QSA)

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 19 / S 1

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this deletion.

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

GroupHPOFreeText: Both (2) patients had RCC, 1 had hemangioblastomas and 1 had retinal capillary hemangioma. These phenotypes couldn’t be paired as it was not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 23 / S 5

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This deletion was found in Family No. 23 with 1 member affected. No other family info was given

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: VHL_15 (tumor ID)

KindredID: 15

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175N (c.523T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756226, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.523T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y175N (c.523T>A)

MultipleGeneVariants: N/A

PatientID: 19

KindredID: F01

Case: F, Age Unknown, Taiwanese

DiseaseAssertion: Asymptomatic

FamilyInfo: A total of 10 members of this family (F01) had a complete deletion of the VHL gene. Four of these patients (16, 18, 21, 33) presented with clinical features of VHL.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19288063

SupplementalData: Figure 1

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of 142.9kb resulted in deletion of the VHL gene.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 4

KindredID: F02

Case: F, Age Unknown, Taiwanese

DiseaseAssertion: Asymptomatic

FamilyInfo: A total of 2 members of this family (F02) had a complete deletion of the VHL gene. One of these patients (3) presented with clinical features of VHL.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of 53.3kb resulted in deletion of Exon 1 in the VHL gene.

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, deletion

PatientID: V95

KindredID: V95

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: p.G104= (c.312C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420538, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.312C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; synonymous_variant

CivicName: G104= (c.312C>G)

MultipleGeneVariants: N/A

PatientID: V89

KindredID: V89

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL Type 2B.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G106Tfs*54 (c.315_316insAC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130208, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.315_316insAC

gnomAD: N/A

VariantEvidence: N/A

MutationType: insertion; plus_2_frameshift_variant

CivicName: G106Tfs*54 (c.315_316insAC)

MultipleGeneVariants: N/A

PatientID: V80

KindredID: V80

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL Type 2B.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely 15300849

SupplementalData: N/A

Variant: p.L140Qfs*3 (c.419_420del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357039, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.419_420del

gnomAD: N/A

VariantEvidence: Reported as c.417del2 and mapped to c.419_420del.

MutationType: deletion; minus_2_frameshift_variant

CivicName: L140fs (c.419_420del)

MultipleGeneVariants: N/A

PatientID: III-9

KindredID: 1

Case: M, 63Y0M, Chinese

DiseaseAssertion: Assumed VHL

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: HP:0005584; HP:0000107; HP:0010797 (Renal cell carcinoma, renal cyst, CNS hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711 (Retinal hemangioblastoma)

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

PatientID: III-4

KindredID: 1

Case: M, 81Y0M, Chinese

DiseaseAssertion: Asymptomatic

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: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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

PatientID: II:2

KindredID: 8

Case: F, 43Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: a 3 generational family found with 5 phenotypically affected members, two of which were confirmed with the exon 1 deletion. This patient and her son were tested to be found with the deletion of exon 1. Her son was found with retinal angiomas at 17Y, pancreatic cysts and epididymal/ovarian cystadenoma at 19Y, and hemangioblastomas at 23Y. Her two sisters and father all had hemangioblastomas; and father also had RCC, however the father and one sister were deceased; and the other sister was not available to provide a DNA sample.

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

CaseHPOFreeText: patient was found with retinal hemangioblastomas at 35Y and hemangioblastomas at 43Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 1 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: exon 1 deletion

MultipleGeneVariants: N/A

PatientID: unknown (sister)

KindredID: 13

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: the patient’s brother was found with hemangioblastomas, RCC, and multiple pancreatic cysts or tumors at 23Y, and retinal angiomas at 24Y. Their mother was found at 43Y with CNS hemangioblastomas, however she died before diagnosis; no DNA sample was available.

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

CaseHPOFreeText: patient had hemangioblastomas, RCC, and multiple pancreatic cysts or tumors diagnosed at 30Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 3 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: exon 3 deletion

MultipleGeneVariants: N/A

Six patients with classic VHL disease (VHL patients) and 6 healthy control participants took part in the study. The patients were free from any associated neoplasia at the time of the study and had no other medical disorders. One 37Y male VHL patient with unknown phenotype was described to have the p.Asp121His VHL mutation.

PatientID: None

KindredID: 1

Case: F, 28Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No other family members presented any signs of VHL disease. DNA was available from her sister (32 years), brother (29 years) and mother (55 years). The patient’s father died from a myocardial infarction at the age of 58 years. Suggesting de novo but unclear with no test on father

CasePresentingHPOs: HP:0010797, HP:0006880, HP:0001737, HP:0009711 (hemangioblastoma, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseHPOFreeText: at age 28, the patient presented with neurological symptoms from two hemangioblastomas (cerebellar and cerebro-spinal).

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: L140Pfs*4 (c.418dup)

CaseProblemVariantFreeText: N/A

LegacyVariant: c.631_632insC

ClinVar: N/A

CAID: CA432421871 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.418dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: L140fs (c.418dup)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Hemangioblastoma

FamilyInfo: None

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: deletion (deletion on chromosome 3 (>35kb, <90kb) resulting in complete loss of VHL gene)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: germline deletion on chromosome 3 (>35kb, <90kb) resulting in complete loss of VHL gene. Hemangioblastoma from this patient shows a missense mutation R200W(c.598C>T) in the second copy of VHL gene.

MutationType: deletion

CivicName: Deletion AND R200W (c.598C>T)

MultipleGeneVariants: Somatic, VHL, c.598C>T (p.Arg200Trp)

PatientID: VHL-23

KindredID: 23

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

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

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001732 (Hemangioblastoma, Renal cyst, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma and clinical classification: A2.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Null (c.341-?_642+?del)

MultipleGeneVariants: N/A

PatientID: VHL-3

KindredID: 3

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Renal cyst, Renal cell carcinoma)

CaseHPOFreeText: CNS hemangioblastoma and clinical classification: A1.

CaseNotHPOs: HP:0002666; HP:0001732 (Pheochromocytoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V194Afs*61 (c.579_580del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70052556, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.579_580del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant; deletion

CivicName: V194fs (c.579_580del)

MultipleGeneVariants: N/A

43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 1 (patient VHL-7) of the 43 patients was found to have the Arg167Serfs*5 (c.499_504delinsT) germline mutation of the VHL gene. Genotyping was performed on peripheral blood executed via direct sequencing on an automatic sequencer and real time quantitative PCR. Clinical manifestations associated with this mutation include: renal cell carcinoma, retinal hemangioblastoma, and renal cysts. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease.