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

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline p.G93Afs* (c.278delG) mutation, stated in the paper as c.490delG due to an older transcript. It was seen in family [pedigree No] 16, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. RT-PCR analysis in RCC cell lines found a p.R82C (c.244C>T) mutation, stated in the paper as c.457C>T due to an older transcript. It was seen in cell line ACHN. Any family information or other manifestations apart from RCC were unclear.

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

PatientID: 217

KindredID: 81

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's brother had the same germline mutation, and presented with a CNS hemangioblastoma at 20, and a pheochromocytoma at 26. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.

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

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33.

CaseNotHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, 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.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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>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: 13

KindredID: 6

Case: F, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Family #6 is large. The proband (patient 12) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's daughter, patient 13, was asymptomatic at the time of the study.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma )

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

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

PatientID: 115

KindredID: 42

Case: M, 12Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 42) had four family members confirmed with the mutation: his son (CNS hemangioblastoma at 12, retinal angioma at 11); his sister 1 (patient 116) presented with multiple pancreatic cysts/tumors at 53; his niece (daughter of sister 2) was asymptomatic at the time of assessment, and his nephew (son of brother 2) presented with a CNS hemangioblastoma at 12, and pheochromocytoma and multiple pancreatic cysts/tumors at 18. The proband also had three family members who passed away before diagnosis/ before they could be confirmed with the mutation: his sister 2 (patient 117) had multiple pancreatic cysts/tumors at 46, his brother 1 presented with a CNS hemangioblastoma at 47, renal cell carcinoma at 59, and multiple pancreatic cysts/tumors at 59; and his brother 2 presented with a retinal capillary hemangioma at 43, and CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 44.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 36, multiple pancreatic cysts and/or tumors at 40, and retinal angioma and renal cell carcinoma at 44.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336).

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

Variant: p.W117G (c.349T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 862346; https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W117G (c.349T>G)

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. One male patient (patient 226) was found with this germline mutation from family #84. He was diagnosed with CNS hemangioblastoma at 24Y and multiple pancreatic lesions at 26Y. 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 #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

PatientID: 70

KindredID: 24

Case: F, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient no. 69) had the same germline mutation as his mother (patient no. 70). The proband himself presented with renal cell carcinoma at age 34, multiple pancreatic cysts/tumors at age 38, and pheochromocytoma at age 39.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 34.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001737; HP:0001732; HP:0002666 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, 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.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182978, https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: 30Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Recorded as a familial tumor; no other family info present

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma reported with an age at diagnosis of 30 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R167W (c.499C>G)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 2

Case: 15Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Recorded as a familial tumor; One other family member (Patient ID: 5) was a 29 year old patient with a bilateral pheochromocytoma. "Belonging to the same family", although the connection is unclear.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Unilateral pheochromocytoma reported with an age at diagnosis of 15 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R167W (c.499C>G)

MultipleGeneVariants: N/A

PatientID: 28

KindredID: 288

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 288 was mentioned (Patient: 5). This patient was found to have a pancreatic endocrine tumour and pheochromocytoma, without renal cell carcinoma.

CasePresentingHPOs: HP:0030405; HP:0002666 (pancreatic endocrine tumour, pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation: c.272T>A and 273C>A mutations (HGVS nomenclature as c.272_273delinsAA) which leads to this nonsense mutation. It was found in a VHL patient with retinal hemangioblastomas diagnosed at 21Y and cerebellar hemangioblastomas at 23Y. No other family info mentioned.

GroupID: 36

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 of the 573 patients discussed in this paper were found to have the following mutation belonging to 3 families altogether.

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

GroupHPOFreeText: all 4 patients had retinal angiomas diagnosed at a mean age of 30Y and cerebellar hemangioblastomas diagnosed with a mean age of 25Y, and 2 had RCC diagnosed at a mean age of 29Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Y185* (c.555C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223233 https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y185* (c.555C>G)

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: 39

Case: 45Y0M, 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; HP:0005584 (retinal capillary hemangioma; cerebellar hemangioblastoma; renal cell carcinoma)

CaseHPOFreeText: patient had retinal capillary hemangioma diagnosed at 45Y, cerebellar hemangioblastomas diagnosed at 24Y, and RCC at 45Y

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.K196Rfs*59 (c.584_585delAG) 

LegacyVariant: N/A

CaseProblemVariantFreeText: This mutation also automaps to NM_000551.3:c.585_586delGA

ClinVarID: 547831 https://www.ncbi.nlm.nih.gov/clinvar/variation/547831/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: K196fs (c.584_585delAG)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients 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). This mutation (c.472C>G) was found in a VHL type 1 patient pf 21Y old, with retinal hemangioblastomas and cerebellar hemangioblastomas. 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: V-12

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 20

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL; One registrant belonging to family 20 has the germline VHL mutation of c.481C>T.

CasePresentingHPOs: HP:0009711; HP:0000107; HP:0001737 (retinal capillary hemangioma, renal cyst, pancreatic cysts)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0005584 (hemangioblastoma, pheochromocytoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

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

PatientID: None

KindredID: 7

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Reported as familial VHL - no further information provided

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0010797; HP:0001737; HP:0005584; HP:0000107 (pheochromocytoma, hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 1070179 https://www.ncbi.nlm.nih.gov/clinvar/variation/1070179/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 15

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Described are 5 patients with this familial VHL mutation. They belong to family 15 and have the germline VHL mutation of c.500G>A.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0005584; HP:0000107; HP:0001737; HP:0002666; HP:0030393 (retinal capillary hemangioma, hemangioblastoma, renal cell carcinoma, renal cyst, pancreatic cysts, pheochromocytoma, endolymphatic sac tumor)

GroupHPOFreeText: of the totalling 5 members, 3 have rHAB, 3 have cHAB, 3 have renal cysts, 2 have RCC, 2 patients suspected (deafness, tinnitius, or vertigo) for an endolymphatic sac tumor (ELST), 1 has a pheochromocytoma and 1 has a pancreatic cyst. Additionally an adnexal papillary tumor of probable mesonephric origin (APMO) was recorded in this cohort.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: III-23

KindredID: 1

Case: M, Age unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. His mom and grandmother appeared to have the VHL mutation. See family pedigree (Fig. 1).

CasePresentingHPOs: None

CaseHPOFreeText: VHL found by genetic testing not clinical findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: N/A

19 members of a large family were found to harbour the deletion of a single adenosine (A) at nucleotide 688 of VHL gene through genetic testing. Converted to NM_000551.3 standards this is a E160Sfs*10 (c.477delA) mutation. 9 members were genetically confirmed, alongside phenotypic presentations. Patient I.1 had 16 kids, 8 of which were known to have VHL. Southern blot analysis and PCR were performed on germline DNA samples. The proband (I.1), female of age 48, was found to have spinocerebellar ataxia type 2 and subsequently died at age 54 of pneumonia. Two of her children (II.1, II.28) and one grandchild (III.24) were noted as having CNS and renal involvement. Another child (II.5), was reported as having renal involvement. Another daughter (II.13) and a grand daughter (III.38) were noted as having CNS involvement. Her son (II.26), age 34, presented with a haemangioblastoma in the cerebellum. One year later an oesophageal abnormality was found. 10 years later, bilateral clear cell renal cancer and a syrinx associated with a spinal cord haemangioblastoma were found. He had baseline tachycardia and cystic lesions in the pancreas. A scrotal ultrasound examination showed he had a multicystic mass above his left testis consistent with epididymal cystadenoma. Haemangioblastomas posterior to the medulla with cysts splaying the medulla were also reported as well as cervical and thoracic spine hemangioblastomas. Finally, the probands grand-daughter (III.9), age 32, had a history of retinal angiomas since teen years and retinal detachment at the age of 23. She had olivopontocerebellar atrophy since her mid-late 20's due to new onset slurred speech and illegible handwriting and cysts of the pancreas and kidney detected at 22 years. She also presented multiple renal cysts without renal tumours, neuroendocrine/islet cell carcinoma (mass in the tail of the pancreas) and liver metastatic foci. Neuroimaging showed diffuse cerebellar and brain stem atrophy with slight atrophy of the cervical cord. A neurological exam revealed ataxia, dysarthria, dysmetria, and bulbar signs. She and various members of this family were also found to have abnormal increase in CAG repeats (41 instead of the normal 15-29) in one allele of her ataxin-2 gene (SCA2). ACMG evidence codes: 'PP1' since we have cosegregation with the disease in multiple affected family members, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 45

KindredID: 45

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0001737, HP:0010797 ( pancreatic cysts, hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0006770, HP:0009711, HP:0000107 (pheochromocytoma, clear cell renal cell carcinoma, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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: 356

KindredID: 356

Case: Sex Unknown, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

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

CaseHPOFreeText: CNS hemangioblastoma and pancreatic cyst or tumor.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete 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 R161G (c.481C>G) germline missense mutation of the VHL gene was found in a 27 year old VHL patient with no family history, hemangioblastomas of the central nervous system and retinal hemangioblastomas and pheochromocytoma, and renal cysts (index case 5).

PatientID: 173

KindredID: 173

Case: Sex Unknown, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Pancreatic cyst or tumor and clear cell renal cell carcinoma and renal cyst.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (3kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 3kb

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 29

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation belonging to VHL family 29

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

GroupHPOFreeText: both (2) patients have retinal capillary hemangiomas, hemangioblastoma, and pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q (c.533T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L178Q (c.746T>A)

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: allele-specific oligonucleotide (ASO) probes and hybridization conditions confirmed

MutationType: missense_variant; transversion

CivicName: L178Q (c.533T>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 missense mutation was found in a German, VHL type 1 patient with retinal angiomas (family VHL 59). The H115Y (c.343C>T) mutation was detected in the patient, referred to in the paper by c.556C>T due to a difference in transcript sequence.

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: 49 (Cousin)

KindredID: 18

Case: F, 62Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666; HP:0009711; HP:0005584; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: This patient presented with retinal angioma (18Y) and pheochromocytoma (20Y). Age of diagnosis of CNS hemangioblastoma and renal cell carcinoma is unknown.

CaseNotHPOs: HP:0000077; HP:0001732 (Abnormality of the kidney, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

20 vHL families were retrospectively identified in SickKids Genetics and Cancer Genetics Program SHIRE genetics database, with data entered between 30 August 1984 and 8 August 2016. Family 19 had 5 members confirmed with the stop gained mutation c,263G>A (stated as c.476G>A in the paper which used the Latif sequence as reference). The proband (male), cousin (female), and first cousin once removed (male) did not have any manifestations and their last known age was 12Y, 8Y and 27Y respectively. The uncle was found with hemangioblastoma at 28Y and died at 29Y. The mother was found with hemangioblastoma; renal cell carcinoma; pancreatic cysts/tumors; renal cysts/tumors and had an age of onset of 17Y and was 33Y at the time of the study. This family was later published in 31368132.

Of 246 patients affected with von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene was determined from peripheral blood. Family 6101 was found with p.Tyr112His mutation in the VHL gene (legacy notation c.547T>C converted to NM_000551.3): one patient was in this family with pheochromocytoma, and retinal angioma. No other family information was provided.

GroupID: 6102

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Each group represents a family.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)

GroupHPOFreeText: 1/3 members with pheochromocytoma, 3/3 members with CNS hemangioblastoma, 3/3 members with retinal angioma and 2/3 members with RCC. Diagnosed as a VHL Type 2B family.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114R (c.340G>C)

LegacyVariant: c.553G>C

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 553, G to C (Gly to Arg), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.340G>C, p.Gly114Arg (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

GroupID:N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 301 were enrolled to evaluate the natural history of vHL-associated pancreatic lesions. Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study.

CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93V (c.278G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625232 https://www.ncbi.nlm.nih.gov/clinvar/variation/625232/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:G93V(c.278G>T)

MultipleGeneVariants: N/A

PatientID: V64

KindredID: V64

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.E73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164, https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

CivicName: E73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: V60

KindredID: V60

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four unaffected family members were tested and found to be negative. No other family history was available.

CohortInfo:92 unrelated patients with VHL disease.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q(c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:R161Q(c.482G>A)

MultipleGeneVariants: N/A

PatientID: V265

KindredID: V265

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.Y156C (c.467A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43600, https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y156C (c.467A>G)

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

KindredID: 17

Case: Sex Unknown, 26Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 other family members were found to have this VHL variant. Patient 17-I was asymptomatic. Patient 17-II presented with CNS hemangioblastoma (8Y).

CasePresentingHPOs: HP:0009711; HP:0001737 (Retinal capillary hemangioma, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with 6 pancreatic cysts (15Y) and retinal hemangioblastoma (16Y). Age at the end of study: 26Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

PatientID: I

KindredID: 7

Case: Sex Unknown, 40Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: One other family member presented with this variant and was asymptomatic.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 4Y. presented with 3 retinal hemangioblastomas (8Y, 16Y). Age at the end of study: 40Y.

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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

KindredID:52

GroupID: 6

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.52 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: c.407C>T (p.S136L)

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence:

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

PMID: 21103895

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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

GenotypingMethod: N/A

SamplingMethod: N/A

PatientID: None

KindredID: 1

Case: M,53Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient had a family history of VHL.

CasePresentingHPOs: HP:0006880, HP:0009713, HP:0010797, HP:0000238,HP:0005584, HP:0032241, HP:0030405, HP:0002666 (cerebellar hemangioblastoma, spinal hemangioblastoma, hemangioblastoma, Hydrocephalus, renal cell carcinoma, Cervical neoplasm, pancreatic endocrine tumour, pheochromocytoma)

CaseHPOFreeText: At age 51, he was found to have three cerebellar hemangioblastomas (two left-sided cerebellar hemangioblastomas (LHB1, LHB2) and one right-sided cerebellar hemangioblastoma (RHB1), two supratentorial hemangioblastomas (right frontal, suprasellar), and multiple spinal HBs including a large left C7-T1 lesion (C7T1), a T5 (T5), right and left sided T11 lesions (RT11, LT11), L2-3 lesion (L23), and multiple small nerve root lesions of the cauda equine consistent with CNS HBs. An oncologic workup revealed bilateral RCC (grade III clear cell), pheochromocytoma requiring adrenalectomy, and a pancreatic neuroendocrine tumor. The patient was subsequently started on Pazopanib. Twelve months following initiation of therapy, the C7T1 HB decreased in size from 14 mm to 12 mm as measured on post-contrast axial T1 MRI. Six months later, C7T1 was further decreased to 9.5 mm, resulting in an approximately 50% decreased volume from initiation of treatment and notably reducing the mass effect on the spinal cord. The L23 lesion also demonstrated reduced size during this time period, from 8 mm to 7.5 mm, while the remaining HBs and retroperitoneal lymph nodes remained stable or increased in size. Following 21 months of TKI therapy, the patient’s systemic disease was stable, and he was placed on a drug holiday. Six months following cessation of Pazopanib, many of the CNS HBs increased slightly, including the C7T1 lesion.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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: 34628056

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 4

KindredID: 4

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: retinal capillary hemangioma

FamilyInfo: N/A - family history was unremarkable. The paper states however that this patient inherited the duplication from a nonsymptomatic parent.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: a 16- year-old girl referred to this center for VHL testing due to an isolated retinal angioma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.*1149A>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130264 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573130264

gnomAD: N/A

VariantEvidence: Quantitative Southern blot/real-time quantitative PCR analyses was normal in this patient. Known polymorphic variant on the 3’UTR of the VHL gene, as well as the 5’UTR. PCR–RFLP assay approach showed that both alleles were expressed in apparently equimolar amounts (Fig. 2d) suggesting that the 11 bp duplication has no effect on expression of the affected allele.

MutationType: 3_prime_UTR_variant

CivicName: c.–65_–55dup11 AND 3' UTR alteration (c.*1149A>G)

MultipleGeneVariants: Germline, VHL, c.–65_–55dup11

PatientID: II/3

KindredID: 2

Case: M, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: A patient was found to have a mutation in the VHL gene (R167W (c.499C>T)). The patient inherited this mutated gene from his father (I/1) who had haemangioblastoma. His brother (II/2) also manifested renal carcinoma, central nervous system haemangioblastoma, pheochromocytoma and pancreatic cysts. One of his two children (III/3) also developed the disease. Pedigree: see Figure 2.

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant:R167W (8702C>T)

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

CAID: CA020450 (http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET)

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: Fetus 2 (of proband)

KindredID: 9

Case: Fetus, sex unknown, Chinese

DiseaseAssertion: N/A

FamilyInfo: Positive - Family history of RCC and Pheo; Parent had CNS hemangioblastoma presenting at 26Y. In prenatal diagnosis, two fetuses (1 & 2) were positive for the mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: 55Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive -- Their father and brother both had the same germline mutation. Their father was screened after genetic testing and found to have a left RCC with lung metastasis at age 80, and their brother was asymptomatic.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma first presenting at 55Y

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009715 (renal cell carcinoma, pheochromocytoma, Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R107G (c.319C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

GroupID: 49

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.496G>T germline variant of the VHL gene. Member 2046 had no renal involvement. Member 1258 presented with mild renal disease. 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 (Renal neoplasm)

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]).

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 2 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

GroupID: 21

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to harbor the c.340G>C germline variant of the VHL gene. Members 1070 and 744 had unknown renal involvement. Member 742 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:0005584 (Renal cell carcinoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 2 individuals with this mutation are reported. It is unclear if one or both of these previously reported individuals correspond to members of the current family.

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

Variant: p.G114R (c.340G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that this mutation is predicted to disturb the splicing process.

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>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.K159Efs*15 (c.473dup) germline variant of the VHL gene was detected in an individual (ID 5299, Family 235). They presented with 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]). Individual RCC phenotype is noted as negative. The paper states that this individual is previously reported in PMID 12202531 and/or 9829912.

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.S65L (c.194C>T) germline variant of the VHL gene was detected in an individual (ID 3404, Family 209). This patient presented with renal cell carcinoma. No family information is provided. This patient was previously published in PMID 9829912.

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

GroupID: 17

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 3 patients with a F76del (c.227_229del) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There were 3 patients reported with the p.F76del (c.227_229del) mutation. All 3 members presented with retinal hemangiomas, while no other clinical manifestations were discussed. Additionally, no family information was provided.

PMID: N/A

Reference: Daniele S., Pelliccioli G.P., Daniele C., Mandich P., Montera M., Simoncelli C., et al (1996). Von Hippel-Lindau disease in twins: Clinical and molecular study. European Journal of Neurology, 3(6), 581-587. https://doi.org/10.1111/j.1468-1331.1996.tb00276.x

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.C162Y (c.485G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223225, https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 1

Case: M, 35Y0M, African American

DiseaseAssertion: VHL

FamilyInfo: No family information provided. Patient’s had previous genetic testing that confirmed his genetic variant.

CasePresentingHPOs: HP:0030072; HP:0010797 (Paranasal sinus neoplasm, hemangioblastoma)

CaseHPOFreeText: Patient with known VHL disease presented with Sinonasal renal cell-like adenocarcinoma (SNRCLA). He also had a history of multiple CNS and visceral tumors consistent with VHL disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161P (c.482G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756111, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.482G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R161P (c.482G>C)

MultipleGeneVariants: Somatic, MSH6, c.1867C>G (p.Pro623Ala); Somatic, MST1R, (p.Val772Met); Somatic, PIK3C2B, (p.His660Arg)

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation (L188P (c.563T>C)) was found in a VHL patient with retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. This is possibly previously published in PMID: 15300849

PatientID: None

KindredID: 4479

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.E70* (c.208G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.E70* (c.421G>T)

ClinVarID: 428806 https://www.ncbi.nlm.nih.gov/clinvar/variation/428806/

CAID: CA16602179 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.208G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E70* (c.208G>T)

MultipleGeneVariants: N/A

GroupID: 3575

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

GroupHPOFreeText: 2/3 members had retinal angiomas (hemangiomas), 1 had CNS hemangioblastoma and 1 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.448delA)

CaseProblemVariantFreeText: NM_000551.3:c.448delA adjusts to up to date to NM_000551.4:c.449delA

LegacyVariant: p.221fs (c.661delA)

ClinVarID: 195093 https://www.ncbi.nlm.nih.gov/clinvar/variation/195093/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.448delA)

MultipleGeneVariants: N/A

GroupID: 3624

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

GroupHPOFreeText: 2/3 members had retinal angioma (hemangioma), 2/3 had CNS hemangioblastoma, and 1 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 1 3624NCI)

SupplementalData: N/A

Variant: p.R176Gfs*26 (c.526delA)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R247fs (c.739delA)

ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: R176fs (c.526del)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation was also found in a VHL type 1 family of 27 individuals (family ID 3003), using PCR and SSCP sequencing. The mutation of c.502_503insTTGTTCGT was referred to in the paper by c.715insTTGTTCGT due to a difference in transcript sequence. Five of 11 individuals were identified with renal cell carcinoma, 11 with retinal hemangioblastomas, and 9 with CNS hemangioblastomas. Previously published in PMID 8956040 (type 1 3003NCI); and PMID 9829911. ACMG codes as follows: PVS1 a frameshift variant in a gene where loss of function is a known mechanism of disease.

GroupID: 3314

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

GroupHPOFreeText: 2/3 members had retinal angioma (hemangioma), 2/3 had CNS hemangioblastoma, and 1 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L249P (c.746T>C)

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 108

Case: M, 30Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: Positive for familial antecedents. Family history of cerebellar hemangioblastoma.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: Germline IRAK2 (unclear if partial or complete) and ENST197804 gene deletions. Loss of exons 2-3 of HSPC300. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, IRAK2, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, HSPC300, Exon 2-3 Deletion

PatientID: None

KindredID: 93

Case: M, 31Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: Positive for familial antecedents. Family history of renal cysts and clear cell renal cell carcinoma.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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: Germline HSPC300 retention. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

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

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 (W88R (c.262T>A)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 1255NCI. It was reported in the paper as c.475T>A 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. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

GroupID/ KindredID: 13F, 564NCI, 1239NCI

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 and the National Cancer Institute database, with an unknown number of members belonging to Family IDs 13F, 564NCI, 1239NCI. 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; 9829911

SupplementalData: N/A

Variant: p.W117C (c.351G>T)

LegacyVariant: p.W117C (c.564G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W117C (c.351G>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 (L153fs (c.457delC)) was taken from the Cambridge, Department of Pathology database. It had an unknown number of members belonging to Family ID 41CA, reported in Table 3, as being found in VHL families without pheochromocytoma, and with renal cell carcinoma. Additionally, it was reported in table 5, specified as families without detailed clinical information, under family ID 99CA. It was reported in the paper as c.670delC due to a difference in transcript reference.

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 (K159fs (c.473dupT)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 6BMS. It was reported in the paper as c.685insT due to a difference in transcript reference. Table 5 lists all ID and mutations associated with individuals without detailed clinical information. Other phenotypes are possible, however not detailed here.

PatientID: II-4 (index case)

KindredID: 1

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: assumed VHL

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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: No genetic testing was done prior to death, however family history and presentation leads to this deduction

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: 96

KindredID: None

Case: Age and Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0000107 (hemangioblastoma, pancreatic cysts, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666; HP:0030405; HP:0030393 (Renal cell carcinoma, Retinal capillary haemangioblastoma, Pheochromocytoma, Pancreatic endocrine tumour, Endolymphatic sac tumour)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; See Suppl 1 (Supporting table)

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA020466 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.525C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 7

Case: Sex unknown, Age unknown, French

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.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France (c.525C>G).

GroupID: 12

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant from France 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.R113* (c.337C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: 10

KindredID: 10

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: N/A - not stated

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: A pheochromocytoma (PCC) diagnosed first at 11Y was found, with follow up of a 15 year duration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: c.340+682T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 964770 https://www.ncbi.nlm.nih.gov/clinvar/variation/964770

CAID: N/A

gnomAD: N/A

VariantEvidence: Tumor analysis was performed since there was a paraffin embedded sample. Patient 10 did not have loss of heterozygosity, but was found to have a somatic variant in the exon 3 of VHL (c.482G>A; p.Arg161Gln). This was the only patient observed to have a cluster of tumor cells with a positive membranous CA9 immunostaining, this can be seen in VHL-related PPGL. CA9 is a protein reported to influence regulation cell proliferation and tumor progression and is known to be expressed at the membrane of tumour cells in the case of VHL inactivation can be seen in VHL-related PPGL. Subsequently as expected, the PPGL of patient 10 had a significantly low expression of VHL E1-E1' mRNA VHL and PNMT mRNA compared to VHL-tumours used as controls. This suggests that the two VHL variants change the VHL mRNA splicing.

MutationType: splice_site_variant

CivicName: Splice Site (c.340+682T>C); intron_variant

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

PatientID: 3

KindredID: 2

Case: F, 71Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: A family pedigree is provided. Patient’s daughter and granddaughter have the same mutation. Patient’s daughter had a retinal capillary hemangioma and lamellar macular hole in the left eye. The granddaughter did not seem to be affected.

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has tumours, but which she has were not specified (table 1).

CaseNotHPOs: HP:0001737 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have retinal capillary hemangiomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P192L (c.575C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526677, https://www.ncbi.nlm.nih.gov/clinvar/variation/526677/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P192L (c.575C>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: PCR amplification of the coding regions and exon-intron boundaries followed by Sanger sequencing

SamplingMethod: Whole blood

Of 31 Brazilian patients, one was found to harbour the c.540delC (p.I180Mfs*22) mutation of the VHL gene. Genomic DNA was extracted and all VHL coding regions were analyzed by Sanger sequencing. MLPA was performed to investigate large deletions using SALSA® MLPA® P016 VHL probe mix. Data analysis was performed with Genescan 3.7. This patient, age 14, presented with CNS and retinal hemangioblastoma. It is not clear if this mutation is familial.

PatientID: 22

KindredID: 15

Case: Sex Unknown, 19Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: none

CasePresentingHPOs: HP:0010797; HP:0001737 (hemangioblastoma, pancreatic cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668, HP:0002666; HP:0009711; HP:0030405; HP:0005584; HP:0000107 (Paraganglioma, pheochromocytoma, retinal capillary hemangioma, pancreatic endocrine tumor, renal cell carcinoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

PatientID: 10

KindredID: 4

Case: M, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other family members were found to have the same mutation (Patients 6,7,8,9).

CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor)

CaseHPOFreeText: The patient was diagnosed with a pancreatic endocrine tumor at age 13 it was found to be 0.7cm in size. He was diagnosed with pheochromocytoma and paraganglioma at age 12. He was found to have a right side pheochromocytoma measuring 5.5 cm and a left side pheochromocytoma measuring 1.5 cm. He was also found to have a paraganglioma measuring 2.2 cm.

CaseNotHPOs: HP:0009711, HP:0001737, HP:0000107, HP:0005584, HP:0010797 (retinal capillary hemangioma, pancreatic cysts, renal cyst, renal cell carcinoma, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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.500 G >A)

MultipleGeneVariants: N/A