PatientID: 11

KindredID: 11

Case: 30Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: No family history

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0001737 (hemangioblastoma; retinal capillary hemangioma; renal cyst; pancreatic cysts)

CaseHPOFreeText: Aged 30Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS angiomas, retinal angiomas, renal cysts and pancreatic cysts all diagnosed at 30Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 22

KindredID: 22

Case: 13Y0M, Sex Unknown, Argentinian

DiseaseAssertion: hemangioblastoma

FamilyInfo: No family history

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Aged 13Y at diagnosis (genetic testing); does not fulfil type 1 VHL clinical diagnosis. Solitary CNS angiomas diagnosed at 13Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: did not develop other manifestations of the disease during a 5- year follow-up.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88* (c.264G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 936684 https://www.ncbi.nlm.nih.gov/clinvar/variation/936684/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.264G>A)

MultipleGeneVariants: N/A

GroupID: 23

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 41 non-related patients with retinal angiomatosis between 1988 and 1999 were evaluated.

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

CaseProblemVariantFreeText: N/A

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

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: 22

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group of 2 people has clinically confirmed VHL disease. This family were found to harbour the c.481C>T variant (noted in the paper as c.694C>T due to Latif reference transcript being used).

GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease. No VHL clinical phenotypes were explicitly stated other than retinal capillary hemangioma in one patient.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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: None (13)

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This family group of 2 individuals have clinically confirmed VHL disease. These individuals were found to harbor a c.280G>T variant causing a Glu94* missense mutation (noted in the paper as c.493G>T due to Latif reference transcript being used).

GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease. No VHL clinical phenotypes were explicitly stated other than retinal angiomatosis in at least one patient.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E94* (c.280G>T)

LegacyVariant: c.493G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 584477, https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: E94* (c.280G>T)

MultipleGeneVariants: N/A

PatientID: III:4

KindredID: 1

Case: M, 56Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

CasePresentingHPOs: HP:0006880; HP:0002666 (cerebellar hemangioblastoma; pheochromocytoma)

CaseHPOFreeText: patent had a combination of cerebellar HB and bilateral pheo, age of onset at 38Y, and operated on the same year

CaseNotHPOs: HP:0006880; HP:0002666; HP:0030405; HP:0001737; HP:0000107; HP:0002668 (pancreatic endocrine tumor, pancreatic cysts, renal cysts, paraganglioma)

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: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 2656

Case: F, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of her family (patient 8) also presented with pancreatic endocrine tumour.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with one pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V62Cfs*5 (c.180delG)

LegacyVariant: p.V62Cfs*5 (c.393delG)

CaseProblemVariantFreeText: N/A

ClinVar: 182986 https://www.ncbi.nlm.nih.gov/clinvar/variation/182986/

CAID: CA020069 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.180delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V62Cfs*5 (c.180delG)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 1112

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (Pancreatic endocrine tumor)

CaseHPOFreeText: The patient presented with one pathologic pancreatic neuroendocrine tumour at age 32. The tumour had metastasized.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant:p.E160Sfs*10(c.688delA)

CaseProblemVariantFreeText: N/A

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

PatientID: 9

KindredID: AD

Case: F, 38Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737 (Pancreatic cysts)

CaseHPOFreeText: Multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0030393; HP:0009711; HP:0010797 (Renal cell carcinoma, Pheochromocytoma, Endolymphatic sac tumor, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114D (c.340+1G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223190, https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transition

CivicName: G114D (c.340+1G>A) and c.340+5G>C

MultipleGeneVariants: N/A

PatientID: 3

KindredID: JK

Case: M, 40Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: One 5 year old female relative (unknown relationship) with the same heterozygous mutation was asymptomatic.

CasePresentingHPOs: HP:0001737, HP:0010797, HP:0009711, HP:0005584, HP:0030393 (pancreatic cyst, hemangioblastoma, Retinal capillary hemangioma, renal cell carcinoma, endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

GroupID: 3770

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 6 family members recorded with this mutation.

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

GroupHPOFreeText: all members had CNS hemangioblastomas, 5 have RCC and 4 members had retinal angioma (hemangioma)

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.E186* (c.556G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.E257* (c.769G>T)

ClinVarID: 381602 https://www.ncbi.nlm.nih.gov/clinvar/variation/381602/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E186* (c.556G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4398

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78H (c.232A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N149H (c.445A>C)

ClinVarID: 625225 https://www.ncbi.nlm.nih.gov/clinvar/variation/625225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78H (c.232A>C)

MultipleGeneVariants: N/A

GroupID: 3708

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

GroupHPOFreeText: both (2) members has RCC and 1 member had hemangioblastoma

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L255P (c.764T>C)

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 21CA, 56CE

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 two databases: the Cambridge, Department of Pathology database and the Munich, university of Freiburg and Institute of Pathology database. There was an unknown number of members belonging to Family IDs: 21CA and 56CE. 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.Q195* (c.583C>T)

LegacyVariant: p.Q195* (c.796C>T)

CaseProblemVariantFreeText: 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/ KindredID: 8CE, 59CA, 21CE

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 and the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family IDs 8CE, 59CA, 21CE. 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.L89P (c.266T>C)

LegacyVariant: p.L89P (c.479T>C)

CaseProblemVariantFreeText: 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

GroupID/ KindredID: 91CA

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 91CA. 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.L158V (c.472C>G)

LegacyVariant: p.L158V (c.685C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 567944 https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3708NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3708NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: p.L184P (c.764T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 12BMS

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: Family 12BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65* (c.194C>A)

LegacyVariant: p.S65* (c.407C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 223161 https://www.ncbi.nlm.nih.gov/clinvar/variation/223161/

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

CivicName: S65* (c.194C>A)

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: F, 30Y0M, Vietnamese

DiseaseAssertion: VHL

FamilyInfo: None - The diagnosis of VHL had not been established in her parents or her relatives, who lived in Vietnam without further evaluation.

CasePresentingHPOs: HP:0009711; HP:0001737 (retinal capillary hemangioma; pancreatic cysts)

CaseHPOFreeText: At 28Y presented with multiple retinal capillary hemangioma (complicated tractional retinal detachment and multiple large angiomas) and multiple pancreatic cysts. Underwent PPV combined with relaxing retinectomy.

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: DHPLC 1

KindredID: 1

Case: M, 51Y0M, Unknown Ethnicity

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s daughter (DHPLC 1) had a pheochromocytoma at 11Y. At 18Y, she had a pheochromocytoma in the contralateral adrenal gland and two concurrent paragangliomas of the abdominal aorta and urinary bladder. At 25Y, she was found to have a right frontal meningioma. A family history obtained from his daughter’s other parent, one son and one other daughter (not DHPLC 1) was uninformative. The patient’s relatives (except for his daughter) were normal both clinically and biochemically.

CasePresentingHPOs: HP:0001028; HP:0000277; HP:0009715; HP:0000107 (Angioma, abnormality of the mandible, papillary cystadenoma of the epididymis, renal cyst)

CaseHPOFreeText: The patient had an attenuated VHL phenotype caused by mosaicism which led to what initially appeared to be a de novo mutation in his daughter (DHPLC 3). The patient was found to have an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas at age 43Y. Abdominal ultrasonography and total-body magnetic resonance imaging (MRI) conducted at the time of the study (51Y) revealed a 2.3-cm cyst in his right kidney. His blood pressure and levels of plasma free metanephrines, fractionated urinary metanephrines, chromogranin A were normal.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R161Q (c.695G>A)

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q(c.482G>A)

MultipleGeneVariants: N/A

PatientID: V209

KindredID: V209

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.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: V48

KindredID: V48

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.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: V240

KindredID: V240

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL Type 2A.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

GroupID: V32

DiseaseAssertion: VHL

GroupSize:2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Two family members had the same VHL gene mutation.

FamilyInfo: Positive.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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: 10

KindredID: 10

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0100634; HP:0009711 (hemangioblastoma, neuroendocrine neoplasm, retinal capillary hemangioma)

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma, a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm), and a retinal hemangioblastoma.

CaseNotHPOs: HP:0030421; HP:0006770; HP:0030405 (epididymal tumour, clear cell renal cell carcinoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: Patient was recorded without the manifestations of: an epididymal tumor, CCRCC, and a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm)

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

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: 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

PatientID: 63

KindredID: 63

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405; HP:0100634 (pancreatic neuroendocrine neoplasm, Neuroendocrine neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0009711; HP:0030421; HP:0006770 (hemangioblastoma; retinal capillary hemangioma; Epididymal neoplasm, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 7 - see here for more info)

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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

PatientID: 62

KindredID: 62

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0030405; HP:0009711; HP:0030421; HP:0006770 (hemangioblastoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma; Epididymal neoplasm, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 7 - see here for more info)

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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

PatientID: 66

KindredID: 66

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL (asymptomatic)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0030421; HP:0009711; HP:0030405; HP:0006770; HP:0100634; HP:0010797 (epididymal tumour, retinal capillary hemangioma, pancreatic endocrine tumour, clear cell renal cell carcinoma, neuroendocrine neoplasm, hemangioblastoma)

CaseNotHPOFreeText: patient was not recorded to have an epididymal tumor, a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm), CCRCC, a neuroendocrine neoplasm (pheochromocytoma/paraganglioma), nor a CNS hemangioblamstoma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

PatientID: 29

KindredID: 29

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030405; HP:0030421 (Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

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

LegacyVariant: p.P157L (c.470C>T)

CaseProblemVariantFreeText: converted from legacy notation c.470C>T; Pro157Leu; authors contacted

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46 **

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: ** Patients 46, 50, 71, and 72 were reported previously in Aronoff et al, 2018 (PMID: 29437867) as family 5

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: CNS hemangioblamstoma

CaseNotHPOs: HP:0030421; HP:0009711; HP:0030405; HP:0006770; HP:0100634 (epididymal tumour, retinal capillary hemangioma, pancreatic endocrine tumour, clear cell renal cell carcinoma, neuroendocrine neoplasm)

CaseNotHPOFreeText: patient was not recorded to have an epididymal tumor, a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm), CCRCC, nor a neuroendocrine neoplasm (pheochromocytoma/paraganglioma)

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

atientID: II.1

KindredID: F6

Case: M, 0Y6M, Ethnicity Unknown

DiseaseAssertion: Splenomegaly

FamilyInfo: N/A

CasePresentingHPOs: HP:0001744 (Splenomegaly)

CaseHPOFreeText: Diagnosed with splenomegaly at age 6 months (DOB: 2014).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+574A>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1040488, https://www.ncbi.nlm.nih.gov/clinvar/variation/1040488/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: Q164H (c.492G>T) and c.340+574A>T

MultipleGeneVariants: Germline, VHL, c.492G>T (p.Gln164His)

PatientID: II (son)

KindredID: F12

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 4 members of this family (I.mother, II.daughter, II.son, III.granddaughter) presented with pheochromocytoma and were found to have the P138= (c.414A>G) germline variant of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; synonymous_variant

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

PatientID: II.1

KindredID: F1

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: N/A

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and kidney ischemic infarct at age 15 (DOB: 1991).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 816685, https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition; splice_site_variant

CivicName: D143= (c.429C>T) and c.340+770T>C

MultipleGeneVariants: Germline, VHL, c.429C>T (p.Asp143Asp)

PatientID: 84

KindredID: 84

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.R107H (c.320G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223184, https://www.ncbi.nlm.nih.gov/clinvar/variation/223184/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R107H (c.320G>A)

MultipleGeneVariants: N/A

PatientID: 13 (tumour 21)

KindredID: 14

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

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

CAID: CA020246 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EC

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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 9 (tumour 13)

KindredID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one malignant pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

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

CAID: CA020246 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EC

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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 118

KindredID: 42

Case: F, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

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: N/A

CaseHPOFreeText: The proband's niece (daughter of sister 2) was genetically confirmed with the mutation but was asymptomatic at the time of assessment.

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

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. This familial mutation was confirmed in family #42. A male proband (patient 114) was diagnosed with CNS hemangioblastoma at 36Y, retinal angioma at 44Y, RCC at 44Y, and multiple pancreatic lesions at 44Y. His son (patient 115) was diagnosed with CNS hemangioblastoma at 12Y and retinal angioma at 11Y. His first sister (patient 116) was diagnosed with multiple pancreatic lesions at 53Y. His second sister (patient 117), who was not genetically confirmed for the mutation, was diagnosed with multiple pancreatic lesions at 46Y. His niece (daughter of second sister) (patient 118) was asymptomatic. His first brother (patient 119), who was not genetically confirmed for the mutation, was diagnosed with CNS hemangioblastoma at 47Y, RCC at 59Y, and multiple pancreatic lesions at 59Y. His second brother (patient 120), who was not genetically confirmed for the mutation, was diagnosed with CNS hemangioblastoma at 44Y, retinal angioma at 43Y, RCC at 44Y, and multiple pancreatic lesions at 44Y. His nephew (son of second brother) (patient 121) was diagnosed with CNS haemangioblastoma at 12Y, multiple pancreatic lesions at 18Y, pheochromocytoma at 18Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336). Wang et al., 2018 reported 8 patients from 1 family who were genetically confirmed with this germline mutation. Wang et al., 2014 reported 4 patients from 1 family who were genetically confirmed with the mutation. It is likely that all three papers published the same family.

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A female proband, patient 111 from kindred 39, was found with this germline splice site mutation (c.340+5G>C). She was diagnosed with a CNS hemangioblastoma at 35Y. This kindred was likely published in a later paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 107

KindredID: 36

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother presented with a CNS hemangioblastoma and retinal angioma at age 29, but passed away before the mutation could be confirmed.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma and retinal angioma at age 18.

CaseNotHPOs: HP:0005584; HP:0001737; HP:0001732; HP:0002666 (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.H110Pfs*49 (c.329delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 560741, https://www.ncbi.nlm.nih.gov/clinvar/variation/560741/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H110PFS*49 (c.329delA)

MultipleGeneVariants: N/A

PatientID: 37

KindredID: 12

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had the same germline mutation as her brother (the proband) and father. Her brother presented with CNS Hemangioblastoma, Renal cell carcinoma, and multiple pancreatic cysts/tumors at the age of 34. Her father presented with renal cell carcinoma at 55. The patient's uncle passed away before diagnosis and presented with a CNS hemangioblastoma at age 19, but could not be genetically confirmed for the mutation.

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

CaseHPOFreeText: The patient presented with multiple pancreatic cysts/tumors at the age of 27.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Pheochromocytoma, 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.N78S (c.233A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>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. A male patient was confirmed for nonsense mutation in the VHL gene (c.217C>T; p.Gln73*). He was diagnosed with CNS haemangioblastoma at 66Y, retinal angioma at 66Y, renal cell carcinoma at 37Y, and multiple pancreatic cysts or tumours at 54Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336). It is likely that all three papers reported on the same individual.

PatientID: 141

KindredID: 52

Case: F, 69Y0M, Chinese

DiseaseAssertion: VHL

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

CaseHPOFreeText: The proband's mother (patient 141) had a CNS hemangioblastoma and multiple pancreatic cysts/tumors at 66, and renal cell carcinoma at 69.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: 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

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 proband was genetically confirmed with this germline mutation: a 46 year old female from kindred #89 who presented with a renal cell carcinoma at that age. This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 220

KindredID: 82

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister both presented with renal cell carcinoma at ages 49 and 27, respectively. Their mother also had a CNS hemangioblastoma at 45, and their sister had a retinal angioma at 30. No genotyping information was available for either family member.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at age 22, and a pheochromocytoma at age 36.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.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

PatientID: 81

KindredID: 27

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 81) had 3 family members confirmed with the mutation: his aunt 2 (patient 85) had pancreatic cysts and/or tumors at age 50, his cousin/ the son of Aunt 2 was asymptomatic at the time of assessment, and the granddaughter of aunt 2 was also asymptomatic at the time of assessment. The proband also had 3 family members who passed away before diagnosis/ before confirming the mutation: his mother (patient 82) had a CNS hemangioblastoma at 33, his Aunt 1 (patient 83) had a CNS hemangioblastoma at 32, and his cousin/ the son of Aunt 1 (patient 84) had a CNS hemangioblastoma at 30.

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0002666 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: The proband presented with CNS hemangioblastoma at age 28, and renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 38.

CaseNotHPOs: HP:0009711(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.N90I (c.269A>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223172; https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: 160

KindredID: 61

Case: M, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband presented with a renal cell carcinoma at age 44.

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

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: 8

KindredID: 5

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 21 and a multiple pancreatic cysts/tumors at age 30.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, 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.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: None

KindredID: 50

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

PatientID: None

KindredID: 49

Case: F, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

PatientID: None

KindredID: 51

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

CaseProblemVariantFreeText: The protein change was written as Thr175 in the Supplemental but the nucleotide change corresponds to Tyr175.

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 8

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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: 44

KindredID: 44

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0000107 (Retinal capillary hemangioma, Renal cyst)

CaseHPOFreeText: Retinal hemangioblastoma and renal cystic lesion.

CaseNotHPOs: HP:0002666; HP:0010797; HP:0006770; HP:0001732 (Pheochromocytoma, Hemangioblastoma, Clear cell renal cell carcinoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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: 214

KindredID: 214

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transversion

CivicName: S65W(c.194C>G)

MultipleGeneVariants: N/A

GroupID: 47

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have the c.712C>T (R167W) germline variant of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: Number of family affected members is not specified.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151 and/or 8956040

SupplementalData: N/A

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: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 20

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

Variant: p.Q73* (c.217C>T)

LegacyVariant: c.430C>T

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: Q73* (c.217C>T)

MultipleGeneVariants: N/A

GroupID: 88

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.500G>A variant causing a Arg167Gln missense mutation (noted in the paper as c.713G>A due to Latif reference transcript being used). It was noted that this family had patients with pheochromocytoma's.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified. It was noted that this family had patients with pheochromocytoma's.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167Q (c.713G>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

GroupID: 83

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: 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

GroupID: 175

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

Variant: p.V62Cfs*5 (c.180del)

LegacyVariant: c.393delG

CaseProblemVariantFreeText: N/A

ClinVarID: 182986, https://www.ncbi.nlm.nih.gov/clinvar/variation/182986/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: V62Cfs*5 (c.180del)

MultipleGeneVariants: N/A

GroupID: 208

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T105P (c.313A>C)

LegacyVariant: c.526A>C

CaseProblemVariantFreeText: N/A

ClinVarID: 496055, https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: T105P (c.313A>C)

MultipleGeneVariants: N/A

PatientID: 10b

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was positive with 3 other members of unknown relation (10a, 10c, 10d) presenting with the mutation, with various phenotypes, however one member being asymptomatic as of age 3Y.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711; HP:0030405 (Pheochromocytoma; Paraganglioma; Retinal capillary hemangioma; Pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

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

PatientID: 5a

KindredID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: An unspecified relative (5b) has the same familial mutation with renal cell carcinoma, pancreatic, and renal cysts.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0000107 (Hemangioblastoma; pancreatic cyst; renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

PatientID: A-V6

KindredID: A-V6

Case: M, 30Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: 2 affected individuals (twin brothers) in this family but no further details provided. Twin brother of proband died of VHL.

CasePresentingHPOs: HP:0002666; HP:0006880 (Pheochromocytoma, Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar hemangioblastomas and bilateral pheochromocytoma. Diagnosed with VHL type 2.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

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: Variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected to c.499C>T. This assumption was made due to later publications referencing this mutation and paper. Variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected due to future publications' reference to this paper regarding this patient and mutation as c.499C>T

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 7

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 1 individual belonging to 1 family was mentioned with this VHL mutation. No other family info was provided.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Other manifestations aside from pheochromocytoma are possible; but not specified.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: None

KindredID: 160

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 160

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown or unstated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Unknown evidence for phenochromocytoma (neither yes nor no was stated) in this family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N78S (c.446A>G)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 36

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 36

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R177* (c.742A>T)

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

Case: M, 57Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family in India but Ethnicity not explicitly confirmed. Two children with the same mutation. Eldest son presented at age 10 with severe hypertension and bilateral pheochromocytoma. Daughter presented at age 17 with palpitation, blurred vision, blurring vision, bilateral papilledema and bilateral pheochromocytoma. Wife and brother were negative for the mutation.

CasePresentingHPOs: HP:0000822; HP:0002666; HP:0006748; HP:0002315; HP:0001250; HP:0031657 (Hypertension, Pheochromocytoma, Adrenal pheochromocytoma, Headache, Seizure, Abnormal heart sound)

CaseHPOFreeText: Presented at 14 years-old with severe hypertension. On evaluation he was found to have a right adrenal mass with elevated urinary VMA, confirming the diagnosis of a right adrenal pheochromocytoma. Presented at age 22 with severe headache and recurrent seizures. Cardiac auscultation revealed a loud 2nd heart sound and a 3rd heart sound. Examination of the abdomen revealed a palpable mass in the left hypochondrium. This mass was confirmed as a pheochromocytoma. Asymptomatic at age 57.

CaseNotHPOs: HP:0030148 (Heart murmur)

CaseNotHPOFreeText: There were no heart murmurs during evaluation at age 22.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.R82L (c.245G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors carried out analysis of VHL variant p.Arg82Leu with six different in silico tools namely SIFT, I-Mutant3, PhD-SNP, MutPred, PolyPhen2 and SNPs&GO in order to determine the pathogenic potential of the variant.

MutationType: missense_variant;transversion

CivicName: R82L (c.245G>T)

MultipleGeneVariants: N/A

PatientID: II-13

KindredID: 1

Case: F, Age unknown (deceased), Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0002011; HP:0009711 (Morphological central nervous system abnormality, retinal capillary hemangioma)

CaseHPOFreeText: Patient mentioned to have CNS (including retinal) involvement without renal involvement.

CaseNotHPOs: HP:0000077 (Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.688delA

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: SCA2 (an abnormal increase in CAG repeats in one allele of her ataxin-2 gene. This abnormal trinucleotide expansion is consistent with the diagnosis of spinocerebellar ataxia type 2)

PatientID: II-1

KindredID: 1

Case: F, Age unknown (deceased), Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. None of her children or grand/great grand children were recorded with the VHL See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0002011; HP:0009711; HP:0000077 (Morphological central nervous system abnormality, retinal capillary hemangioma; Abnormality of the kidney)

CaseHPOFreeText: Patient mentioned to have CNS (including retinal angiomas) and renal involvement.

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

GroupID: 25

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

GroupID: 36

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.P154L (c.461C>T)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 649525 https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P154L (c.461C>T)

MultipleGeneVariants: N/A

GroupID: 27

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 223172 https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: P1

KindredID: P1

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: Paraganglioma

FamilyInfo: N/A

CohortInfo: Tumour samples and paired peripheral blood samples were obtained from 39 patients, consisting of 31 PCs, seven extra adrenal PGLs and one metastasis from a malignant PC previously presenting with a PC.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: The patient had a malignant extraadrenal paraganglioma measuring 13 mm at age 27.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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: 25

KindredID: 18

Case: Sex Unknown, 35Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405; HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient developed PPGL at 26Y of age, and a PNET at 35Y. They also presented with a CNS HB

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: 26

KindredID: 19

Case: M, 47Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: They had a 14Y family member (ID:27), however their relation is unclear.

CasePresentingHPOs: HP:0002666; HP:0030405; HP:0009711; HP:0000107 (pheochromocytoma, pancreatic endocrine tumor, retinal capillary hemangioma, renal cyst)

CaseHPOFreeText: The patient at 13Y was confirmed with VHL. He developed bilateral pheo at 13Y, which had recurrence at 48M later. He later at 47Y he developed a PNET. He also had renal cysts and retinal HB

CaseNotHPOs: HP:0002668; HP:0001737; HP:0010797; HP:0005584 (paraganglioma, pancreatic cyst, hemangioblastoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T124I (c.371C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 36902 https://www.ncbi.nlm.nih.gov/clinvar/variation/36902/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T124I (c.371C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: A (II-5)

Case: M, 64Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's mother (I:1) died of renal cell carcinoma at age 55. The patient had seven siblings. His brother (II:3) died of cerebellar hemangioblastoma at age 39 and another (II:11), also died of cerebellar hemangioblastoma at age 33. His sister (II:7) was found to carry the mutation and presented with renal cell carcinoma, hemangioblastoma, and pheochromocytoma. Another sister (II:13) who did not undergo genetic testing, presented with hemangioblastoma. Brother (II:1) died of unknown causes and another brother (II:9) was asymptomatic and did not undergo genetic testing. The patient had four children; one was asymptomatic (III:9), another (III:6), the third (III-7) had a retinal angioma had a hemangioblastoma, and a daughter (III-8) had pheochromocytoma. Patient III-8 is the only child from this family who underwent genetic testing and was found to carry the mutation. Some of his nieces and nephews presented with VHL related phenotypes and were found to harbour the mutation. Refer to Figure 1 for family pedigree and information regarding extended family members.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0009711, HP:0002666, HP:0000107 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pheochromocytoma, renal cyst)

CaseHPOFreeText: Diagnosed with renal cell carcinoma at age 42. Underwent radical nephrectomy of both the right and left side. He had five renal cell carcinomas and 15 renal cysts. The patient was on dialysis. He had a satellite lesion.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: F (proband)

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: His mother was also found to have this mutation and she had renal cell carcinoma at age 49.

CasePresentingHPOs: HP:0009711, HP:0002666, HP:0000085 (retinal capillary hemangioma, pheochromocytoma, Horseshoe kidney)

CaseHPOFreeText: Patient developed retinal hemangiomas and unilateral pheochromocytoma at the age of 27 years. Abdominal CT showed also horseshoe kidneys.

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

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

PatientID: P34

KindredID: 1

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: diagnosed at the age of 20 years with VHL and presented with severe hypertension and a 40 mm PC of the right adrenal gland (pheochromocytoma)

CaseNotHPOs: No positive family history

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/ SDHD/ RET/ MEN2

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266 https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: also the polymorphism S69S of the SDHD gene.

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: Germline, SDHD, (p.Ser69Ser)

PatientID: 1 (son)

KindredID: 1

Case: M, 9Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: Familial isolated pheochromocytoma is described as the father is a carrier of the same mutation: R79G (c.235C>G).

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: history of fever, profuse sweating, intense headache and 190/120 blood pressure. He was currently asymptomatic with normal hormonal controls after complete tumor resection of his right adrenals

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988 https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: II-9

KindredID: 1

Case: M, Age Unknown (deceased), Turkish

DiseaseAssertion: asymptomatic

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. This patient’s one child, 4 siblings, and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T) [assumed]

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: This patient passed away before testing however due to siblings and children carrying the same VHL mutation, it can be deduced that he had this variant.

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PatientID: III-1

KindredID: 1

Case: M, 36Y0M, Turkish

DiseaseAssertion: VHL

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s mother, brother, two daughters, and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405 (adrenal pheochromocytoma; renal cell carcinoma; pancreatic endocrine tumor)

CaseHPOFreeText: Right adrenal (nonfunctional) pheochromocytoma, had a history of bilateral adenomectomy due to bilateral pheochromocytoma diagnosed when he was 12. He also has bilateral RCC and pancreatic neuroendocrine tumors

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PatientID: IV-2

KindredID: 1

Case: F, Age Unknown, Turkish

DiseaseAssertion: asymptomatic

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s father, sister, grandmother and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: None - described as a carrier of the p.A149S mutation, with no clinical manifestations. Their asymptomatic work up could have been due to the individual's young age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: F8

Case: Sex unknown, 35Y0M, Spanish

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Multiple lesions were found with the patient’s retinal hemangioma. Age of onset is 35Y0M.

CaseNotHPOs: HP:0006770; HP:0002666 (clear cell renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A