PatientID: 1

KindredID: 26

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: one cerebellar hemangioblastoma was detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V170F (c.508G>T)

MultipleGeneVariants: VHL, Somatic, c.576del13 (p.Asn193Met*9)

GroupID: 1

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. 

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: Exon 1-2 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10182301_10188764del; c.-1231_463+444del6464

MutationType: exon_loss_deletion

CivicName: Exon 1-2 deletion

MultipleGeneVariants: N/A

VHL germline mutation carriers who had an ophthalmologic examination at the Erasmus Medical Centre or the Rotterdam Eye Hospital between 1984 and 2017, and were diagnosed with retinal hemangioblastoma (RH) were included in this study. A diagnosis of RH was based on the clinical appearance of a vasoproliferative retinal tumour. Peripheral blood samples from every member that had clinically suspected VHL disease of each family were collected for VHL mutation analysis. A total of 21 patients from 10 families were included on the basis of both a VHL germline mutation and ocular manifestations. Copy number analyses were carried out by multiplex ligation dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH). Mutations were described as one of the following two groups: truncating (complete deletion, partial deletion, nonsense mutation, splice site mutation, duplication and insertion) or missense. Ocular manifestations were not reported on an individual level, but rather were broken down based on the two groups. From Pedigree (family) 3, one individual was suspected of VHL disease and mutational analysis revealed an in-frame germline P76del(c.227_229del) deletion. This individual had RH development.

PatientID: VHL_2 (tumor ID)

KindredID: 2

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 25Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236, https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 198

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states: Germline, de novo

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: p.W117Cfs*42 (c.351del)

LegacyVariant: N/A

CaseProblemVariantFreeText: paper states c.350delG which automaps to NM_000551.3:c.351delG

ClinVarID: 223197 https://www.ncbi.nlm.nih.gov/clinvar/variation/223197/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: W117fs (c.351del)

MultipleGeneVariants: N/A

ArticleReferenceSequence: NM_000551.3 (Standard)

GenotypingMethod: germline DNA analysis and PCR.

SamplingMethod: tumor tissue

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

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

GenotypingMethod: The entire coding sequence of the VHL gene was amplified in a PCR reaction using primer pairs 3, 101, 102, 103, and 6, 107. Quantitative Southern analysis was then employed.

SamplingMethod: Peripheral blood leukocytes

GroupID/ KindredID: 28

PatientID: II

Case: 24Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

GroupID: 35

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P154P (c.462A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA16621934 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.462A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P154= (c.462A>C)

MultipleGeneVariants: N/A

GroupID: 43

DiseaseAssertion: VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 8 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 3 members are stated to have retinal HBs. Other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: the other 5 patients are said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 31

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.Q132P (c.395A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496063 https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q132P (c.395A>C)

MultipleGeneVariants: N/A

GroupID: 52

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.H191Tfs*11 (c.571delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658795182 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.571delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H191FS (c.571delC)

MultipleGeneVariants: N/A

PatientID: 24

KindredID: 24

Case: 17Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Null (Complete deletion)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Stated in paper as “del VHL”; complete vhl gene deletion

MutationType: deletion (exon_loss_variant)

CivicName: DELETION

MultipleGeneVariants: N/A

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

GenotypingMethod: PCR and multiplex ligation-dependent probe amplification (MLPA)

SamplingMethod: assumed: peripheral blood leucocytes (from PMID: 12114495 described in paper)

PatientID: 19

KindredID: 19

Case: 43Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0030405; HP:0009711 (hemangioblastoma; renal cell carcinoma; pancreatic endocrine tumor; retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Null (Complete deletion)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Stated in paper as “del VHL”; complete vhl gene deletion

MutationType: deletion (exon_loss_variant)

CivicName: DELETION

MultipleGeneVariants: N/A

GroupID: 3003

DiseaseAssertion: assumed VHL

GroupSize: 27

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 27 family members recorded with this mutation.

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

GroupHPOFreeText: 11/27 members had retinal angioma (hemangioma), 9 had CNS hemangioblastoma, and 5 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 1 3003NCI); 9829911

SupplementalData: N/A

Variant: p.S168Ifs*5 (c.502_503insTTGTTCGT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.239fs (c.715insTTGTTCGT)

ClinVarID: N/A

CAID: CA2573051075 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051075

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: S168fs (c.502_503insTTGTTCGT)

MultipleGeneVariants: N/A

GroupID: 3568

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 5 family members recorded with this mutation.

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

GroupHPOFreeText: 1 member stated with an angioma (retinal hemangioma), 2 members have CNS hemangioblastoma, 4 with RCC.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 19464396

SupplementalData: N/A

Variant: p.P86L (c.257C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.P86L (c.470C>T)

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: CA020186 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3760

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Y183* (c.549C>A)

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This mutation was found in 2 Croatian, VHL type 1 family members (family VHL 26). Both have hemangioblastomas of the central nervous system, one has renal cysts, and one with pancreatic cysts.

The authors report this as an AF010238.1:c.443insTCT mutation at codon 77 (insertion Ser). This does not match the associating c. and p. - NM_000551.3:c.230_231insTCT matches Cys77_Asn78insLeu., while c.231_232insTCT (p.Cys77_Asn78insSer) would give the ins Ser the authors write, however this doesn’t match the p.. Without confirmation from authors no assumption could be made.

GroupID/ KindredID: VHL 51

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 6 patients with the given mutation belonging to VHL family 51

GroupPresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, Papillary cystadenoma of the epididymis)

GroupHPOFreeText: CNS hemangioblastomas found in all 6 members of this cohort, and epididimal cystadenomas found in 4 members.

GroupNotHPOs: GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA020131 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.233A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: III-6

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father, the proband (II-4) carried the VHL mutation and presented with clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, and renal cysts. The patient's brother (III-7) carried the mutation but was asymptomatic. The patient's grandmother (I-2) died as a result of pancreatic cancer. His paternal aunt (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another paternal aunt (II-2) underwent surgery for breast cancer. See Figure 3 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Abdominal ultrasound examination of the patient revealed no abnormality.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: F11

Case: Sex unknown, 32Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives

CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangioma)

CaseHPOFreeText: Multiple lesions were found with the patient’s retinal hemangioma. Bilateral pheo. Age of onset is 32Y0M.

CaseNotHPOs: HP:0006770; HP:0000107; HP:0006880; HP:0001737 (clear cell renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, pancreatic cysts)

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 http://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: 8

KindredID: 8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0000107; HP:0005584; HP:0010797; HP:0001737 (Renal cyst, Renal cell carcinoma, Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: Bilateral RCC and renal cysts, CNS hemangioblastoma, positive for pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.N78T (c.233A>C)

LegacyVariant: c.446A>C (N78T)

CaseProblemVariantFreeText: N/A

ClinVarID: 223168, https://www.ncbi.nlm.nih.gov/clinvar/variation/223168/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is declared as “c.446A>C (N78T)” by the authors, this was treated as a legacy variant and mapped to c.233A>C, N78T. This study found coexpression of Epo and EpoR in 11 RCCs and in 10 benign renal cysts in a spectrum of VHL renal disease suggesting that Epo/EpoR coexpression is present in both benign and malignant stages of renal neoplasia. Six benign cysts stained for Epo but not EpoR. The researchers detected loss of heterozygosity of a wild-type VHL allele in different RCCs with microsatellite markers, D3S1110 and D3S2452, flanking the VHL gene

MutationType: missense_variant;transition

CivicName: N78T (c.233A>C)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.509T>G), affecting residue on the surface of pVHL, was found in a VHL family of 4, 3 with retinal hemangioblastomas, 1 with renal cell carcinoma diagnosed at 33Y, and 1 with pheochromocytoma diagnosed at 29Y. This mutation was reported in the paper with an incorrect cDNA written as c.509T>C, however correct translation should be c.509T>G given the Latif et al. (1993): c.722T>G (Val170Gly)

GroupID: 53

DiseaseAssertion: assumed VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 8 of the 573 patients discussed in this paper were found to have identical variants. This mutation (S65W (c.194C>G)) was found in 1 VHL family with 8 patients.

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

GroupHPOFreeText: 6 had retinal hemangioblastoma, 5 had cerebellar hemangioblastomas, and 1 had renal cell carcinoma. Mean ages for each diagnosis follows: 32 (RH), 39 (CHB), 56 (RCC - with one patient)

GroupNotHPOs: HP:0002666 (pheochromcytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation. c.194delC was found in a VHL type 2 family of 7 individuals. Three family members had retinal angiomas, 2 had hemangioblastomas of the cerebellum, 2 had renal cell carcinoma, and one had pheochromocytoma.

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation (c.383T>G), affecting residue within the pVHL protein core, was found in a VHL type 1 family of 3 with 1 patient with retinal hemangioblastomas at 19Y and 1 patient with cerebellar hemangioblastomas at 24Y. ACMG codes as follows: Supporting evidence of pathogenicity because missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2).

PatientID: 6

KindredID: 6

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history but no further details were provided. CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

CasePresentingHPOs: HP:0009711; HP:0006748 (Retinal capillary hemangioma, Adrenal pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL type 2A. Right adrenal pheochromocytoma (41Y) and retinal angioma. No metastasis. Last follow-up 4 years after diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).

SupplementalData: N/A

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

LegacyVariant: c.547T>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors report variant as “547, T to C”. Assumed to be reported in legacy nomenclature (AF010238.1 (Latif et al.)) and mapped to c.334T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: familial history of VHL disease

CasePresentingHPOs: HP:0030393; HP:0010797; HP:0001737 (endolymphatic sac tumor, hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: at 18Y experienced a sudden left hearing loss (MRI revealed hemangioblastomas of the temporal bone invading the otic capsule; operated on; the MTD of the endolymphatic sac tumor at diagnosis was 1.9 cm). The patient also developed pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Q (c.345C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496058 https://www.ncbi.nlm.nih.gov/clinvar/variation/496058/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: H115Q (c.345C>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No family history of VHL disease.

CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0002666; HP:0009726; HP:0001737 (endolymphatic sac tumor, retinal capillary hemangioma, hemangioblastoma, pheochromocytoma, renal neoplasm, pancreatic cysts)

CaseHPOFreeText: patient was 21 years old when he experienced a sudden right hearing loss (cophosis). During a follow-up, the patient suffered from other manifestations of VHL disease mentioned above.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R113* (c.337C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113*(c.337C>T)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (c.464-2A>C) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 4BMS. It was reported in the paper as c.677-2A>C due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (H115Y (c.343C>T)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 59CE. It was reported in the paper as c.556C>T due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 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

PMID: 8956040

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (S72Pfs*87 (c.214delT)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 112CA. It was reported in the paper as c.427delT due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL family without pheochromocytoma, and with renal cell carcinoma.

PatientID: 22

KindredID: 4

Case: F, 8Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four members of this family, IDs #22 (8Y, F), #23 (25Y, M), #24 (14Y, M), #25 (12Y, M), were found to have the same variant and pheochromocytoma.

CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Asynchronous multifocal pheochromocytoma. 8Y at VHL diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 60

KindredID: 23

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 23) had three family members genetically confirmed with the mutation: his son/ patient 61 (asymptomatic at time of assessment), his daughter/ patient 62 (asymptomatic at time of assessment), and his cousin/ the son of his Aunt 3/ patient 68 (CNS hemangioblastoma at 26). The proband also had 5 family members who passed away before they could be confirmed with the mutation: his father/patient 63 (CNS hemangioblastoma at 35, retinal angioma at 35); his sister/ patient 64 (CNS hemangioblastoma at 24 and multiple pancreatic cysts/tumors at 31); his aunt 1/ patient 65 had a CNS hemangioblastoma at 35; his aunt 2/ patient 66 had a CNS hemangioblastoma at 20; and his aunt 3/ patient 67 had a CNS hemangioblastoma at 44.

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

CaseHPOFreeText: The proband presented with CNS hemangioblastoma and retinal angioma at 25, renal cell carcinoma and multiple pancreatic cysts/tumors at 30.

CaseNotHPOs: HP:0002666 (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.W88S (c.263G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2220; https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/?new_evidence=true

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88S (c.263G>C)

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: 162

KindredID: 62

Case: F, 14Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's mother presented with a CNS hemangioblastoma at age 28, and a renal cell carcinoma, multiple pancreatic cysts/tumors, and a pheochromocytoma at age 41.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 14.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: 271

KindredID: 105

Case: F, 42Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented at age 48 with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 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

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: 194

KindredID: 74

Case: F, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 193, has a mother (patient 194) who was also found to have the same germline mutation. The proband had a CNS hemangioblastoma at age 16.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 36.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Renal cell carcinoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, CNS 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.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 146

KindredID: 52

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's nephew (son of sister 2) was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732; HP:0002666; HP:0009711 (Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, 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: c.464-1G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>C)

MultipleGeneVariants: N/A

PatientID: 184

KindredID: 71

Case: M, Age 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother (patient 185) was confirmed with the mutation but was asymptomatic at the time of testing. The proband (patient 184) presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

CaseNotHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, 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) as well as 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.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: dilatation of the cerebral artery

FamilyInfo: None

CasePresentingHPOs: HP:0004944 (dilatation of the cerebral artery)

CaseHPOFreeText: Patient had an intracranial aneurysm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+8C>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 127830 https://www.ncbi.nlm.nih.gov/clinvar/variation/127830/

CAID: N/A

gnomAD: 0.0005055 https://gnomad.broadinstitute.org/variant/3-10188328-C-T

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Region (c.463+8C>T)

MultipleGeneVariants: N/A

PMID: 23434161

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 20034980

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 20

KindredID: MM

Case: M, 35Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0005584 (Pancreatic cysts, Renal cell carcinoma)

CaseHPOFreeText: RCC and multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0010797; HP:0030393; HP:0009711; HP:0002666 (Hemangioblastoma, Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma)

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: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID:1

KindredID: S3

Case: F, 35Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737, HP:0010797 (Pancreatic cysts, Hemangioblastoma)

CaseHPOFreeText: multi-cystic pancreatic lesions and CNS hemangioblastoma

CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666, HP:0030393 (Retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S72P (c.214T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223163 https://www.ncbi.nlm.nih.gov/clinvar/variation/223163/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: S72P(c.214T>C)

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.”

GroupID: 11

DiseaseAssertion: VHL

GroupSize: 14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 14 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0002894; HP:0009711; HP:0010797; HP:0005584 (Neoplasm of the pancreas, Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma)

GroupHPOFreeText: CNS hemangioblastoma (7/14 affected members), renal carcinoma (1/14 affected members) and retinal angioma (2/14 affected members) and pancreatic cystadenoma (number of affected individuals not specified).

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130F (c.388G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant;transversion

CivicName: V130F (c.388G>T)

MultipleGeneVariants: N/A

PMID: 23845641

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: IV-17

KindredID: 1

Case: M, 16Y0M, Iranian

DiseaseAssertion: assumed VHL

FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had a unilateral PCC at 14Y which was surgically removed at the time. Histopathology was benign, and there was no case of relapse or metastatic dissemination.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PMID: 15383938

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 7

KindredID: 7

Case: F, 70Y0M, Taiwanese (East-Asian)

DiseaseAssertion: renal cell carcinoma

FamilyInfo: N/A

CohortInfo: 8 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs1642742 in VHL (c.*294G>A). All but one of these patients (7/8) also presented with the germline variant rs779805 (c.-195G>A) in VHL.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: She had stage IV clear cell renal cell carcinoma with metastasis

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21982469

SupplementalData: Yes - Additional file 1: Figure S1

Variant: c.*294G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 342407 https://www.ncbi.nlm.nih.gov/clinvar/variation/342407/

CAID: N/A

gnomAD: 0.5911 https://gnomad.broadinstitute.org/variant/3-10191943-G-A

VariantEvidence: LOH (G) of this mutation was found in the tumor tissue as well

MutationType: 3_prime_UTR_variant

CivicName: c.-195G>A AND c.*294G>A

MultipleGeneVariants: Somatic, VHL, c.-195G>A

PatientID: 24

KindredID: 24

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Negative family history.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: a carotid body (paraganglioma) was reported with no other details.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

CaseProblemVariantFreeText: Variant is written in paper under p.Tyr152Ile. This is incorrect however is paired to a paper where this variant it described (PMID: 18031321) referencing Thr152Ile, so this was deduced.

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:T152I (c.455C>T)

MultipleGeneVariants: N/A

Twelve patients with hereditary non-SDHx head and neck paragangliomas were analyzed. Eleven of the 12 patients were found to carry germline mutations in the VHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The 39 year old female proband was found to harbour the p.Y156C (c.467A>G) mutation of the VHL gene. She presented with recent onset of hypertension and was diagnosed with a right pheochromocytoma. At age 36, a suspected left pheochromocytoma was noted by CT and increased urinary metanephrines was confirmed at age 39 by MIBG scintigraphy. This imaging showed in addition an uptake located in the neck. MRI confirmed a left adrenal tumor and a left 2cm vagal paraganglioma that was removed and confirmed histopathologically. No other tumor of the VHL spectrum was discovered. Three of her four sons were found to carry the mutation and all underwent clinical screening. One of these sons presented with a 2.4cm abdominal paraganglioma.

PatientID: 11

KindredID: 11

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.T157I

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: 37

KindredID: 37

Case: M, 35Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: Unilateral benign adrenal pheochromocytoma that was operated on at age 26.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488

SupplementalData: N/A

Variant: p.L63P (c.188T>C)

LegacyVariant: L63P (c.401T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2227, https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as L63P (c.401T>C), legacy nomenclature (AF010238.1), and was mapped to p.Leu63Pro (c.188T>C) in accordance with reference sequence NM_000551.3.

MutationType: missense_variant;transition

CivicName: L63P (c.188T>C)

MultipleGeneVariants: N/A

GroupID: 20

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 2 registrants from Germany were grouped in this study via the mutation of c.463+2T>C

GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+2T>C

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 569414 https://www.ncbi.nlm.nih.gov/clinvar/variation/569414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.463+2T>C)

MultipleGeneVariants: N/A

GroupID: 15

Case: Sex unknown, Age unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R120G (c.358A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223199 https://www.ncbi.nlm.nih.gov/clinvar/variation/223199/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R120G (c.358A>G)

MultipleGeneVariants: N/A

GroupID: 26

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 registrants from France were grouped in this study via the mutation of c.486C>G

GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

GroupID: 35

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Two registrants from France both have the same mutation of c.583C>T.

GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 333

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with the c.500G>A germline variant of the VHL gene. Member 9428 presented with mild renal disease. Member 13001 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 10 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously reported individuals/families could alternatively correspond to family 262, 36 or 509.

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

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

ArticleReferenceSequence: AF010238.1 (Legacy Variants- Latif et al.) and NM_000551.3

GenotypingMethod: PCR, SSCP and when abnormal mobility shift was observed, direct sequencing was performed. If no shift was detected or no mutation was found by sequencing, authors proceeded to Southern blotting for detection of large rearrangements.

SamplingMethod: peripheral blood

GroupID: 185

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family are reported as carrying the c.193T>C germline variant of the VHL gene. Member 9359 has unknown renal involvement. Member 9357 presented with mild renal disease. Member 1052 had no renal involvement. Member 3979 has moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 2 patients with this mutation are reported but relation between patients is unknown.

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

Variant: p.S65P (c.193T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 547829, https://www.ncbi.nlm.nih.gov/clinvar/variation/547829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.Y156* (c.468T>G) germline variant of the VHL gene was detected in a family (ID 3). Member 37 had no renal involvement. Member 38 presented with moderate renal disease (RCC). Members 47 and 3 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

GroupID: 44

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family were found to have the germline c.226_228del variant of the VHL gene. Member 4975 presented with moderate renal disease (RCC), members 4978, 4977 and 4976 presented with mild renal disease and member 5283 had unknown renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

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

Variant: p.F76del (c.226_228del)

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.226_228del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: F76del (c.226_228del)

MultipleGeneVariants: N/A

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

PatientID: N/A

KindredID: 16

Case: F, Age Unknown, Brazilian

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

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

CaseHPOFreeText: Patient had VHL disease: CNS-HB, RCC, PCy (see table 1). Previously published 2018 paper (PMID:20567917) reports patient as an Brazilian 24Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20567917

SupplementalData:  N/A

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.227_229delTCT

gnomAD: N/A

VariantEvidence: Variant reported as c.226_228del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 12

Case: M, Age Unknown, Indian

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0001737; HP:0005584 (Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma)

CaseHPOFreeText: Patient had CNS-HB, RCC, Unilateral PH, PCy (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 39Y male

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29124493

SupplementalData:  N/A

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.227_229delTCT

gnomAD: N/A

VariantEvidence: Variant reported as c.224_226del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 13

Case: F, Age Unknown, Indian

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had Unilateral PH (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 45Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29124493

SupplementalData:  N/A

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.227_229delTCT

gnomAD: N/A

VariantEvidence: Variant reported as c.224_226del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient had VHL disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 28388566

SupplementalData:  N/A

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.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: M, 48Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L163P (c.488T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 2231 https://www.ncbi.nlm.nih.gov/clinvar/variation/2231/

CAID: CA020423 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L163P (c.488T>C)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 8

Case: M, 36Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history present.

CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database) [Refer to table 2].

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 deletion

MultipleGeneVariants: N/A

PMID: 32106822

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. Patient no. 31 from family 463 had a missense mutation in the VHL gene (c.551T>A) and presented with pancreatic endocrine tumour and pheochromocytoma. The patient's phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).

PatientID: 5

KindredID: 5

Case: M, 15Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with a peripheral tumor in his right eye at the age of 13. He exited the trial in 2016 with no changes to the tumor size after the administration of propranolol over a one year trial.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Information obtained from Table 2.

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: 27A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183* (c.548C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2215 https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: S183* (c.548C>A)

MultipleGeneVariants: N/A

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 3 patients were found to have the above mutation (c.240T>G). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other 2 patients were stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

PatientID: III-14

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: The transversion mutation was found and confirmed in 4 patients (II-2, III-2, III-6, III-10, III-11) and 3 carriers (III-3, III-9, III-14). At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. Could be assumed and deduced their genetics due to pedigree showing future linear relations of this mutation all in generation III.

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S168T (c.503G>C)

LegacyVariant: p.S168T (c.716G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.503G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: III-7

KindredID: 3

Case: F, Age Unknown, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: The transition mutation was found and confirmed in this patient’s mother (II-3) and 2 carriers, her, and her first-cousin once removed (III-7, IV-2). 5 additional members had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

This study shows the clinical characteristics of three large Chinese families with VHL disease and evaluates the consequence of the genetic test for the diagnosis of VHL disease and clinical screening of the family members. DNA is extracted from peripheral blood in 43 members from three large families with VHL disease and amplified by PCR to three exons of the VHL gene. The PCR products were directly sequenced and the mutations compared with the Human Gene Mutation Database. The ages of the patients who are given the initial diagnosis ranged from 16 to 47 years (mean: 31 years), and the mean time was 17.3 months (2-30 months) from the emergence of the symptom to patients' first visit. Furthermore, the gender distribution was 20% female (4) and 80% male (16). Von Hippel-Lindau disease is seen in 12 members of a Chinese family. Molecular diagnosis is confirmed in only 7 family members. The proband (male; deceased) has retinal capillary hemangioma; hemangioblastoma, 2 of his brothers (deceased) have pancreatic cancer, a third brother has renal cancer and hemangioblastoma, and 5 nephews have hemangioblastoma. There are three members who are asymptomatic carriers, but are young and may be before the age of onset. The mutation p.S168T (c.503G>C) was referred to in the paper by c.716G>C due to a difference in transcript sequence. At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. It could be assumed their genetic mutation due to pedigree showing future linear relations of this mutation all in generation III. ACMG evidence codes: 'PP1' based on segregation results, 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease, 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology.

PatientID: 262

KindredID: 262

Case: Sex Unknown, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive family history for VHL.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001737, HP:0002666, HP:0006770, HP:0000107 (pancreatic cysts, pheochromocytoma, clear cell renal cell carcinoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 207

KindredID: 207

Case: Sex Unknown, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0001732; HP:0002666; HP:0009711; HP:0006770; HP:0000107 (Abnormality of the pancreas, Pheochromocytoma, Retinal capillary hemangioma, Clear cell renal cell carcinoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064, https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

PatientID: 53

KindredID: 53

Case: Sex Unknown, 37Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0001732; HP:0010797; HP:0000107 (Clear cell renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

PatientID: 431

KindredID: 431

Case: Sex Unknown, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS and retinal hemangioblastoma.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0001732; HP:0000107 (Pheochromocytoma, Clear cell renal cell carcinoma, Abnormality of the pancreas, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant; deletion

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The L153P (c.458T>C) germline missense mutation of the VHL gene was found in a 36 yr old VHL patient with renal cysts as well as central nervous system and retinal hemangioblastoma (index case 191).

PatientID: 83

KindredID: 83

Case: Sex Unknown, 11Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0009711; HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Retinal capillary hemangioma, Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (4.6kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Partial deletion of 4.6kb)

MultipleGeneVariants: N/A