Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 20 has one affected member. Genetic analysis reveals mutation R161*(c.481C>T) in the VHL gene. The patient has a family history of VHL disease and presented with retinal capillary hemangioma, renal cyst and pancreatic cysts. ACMG: 'PP4' because the patient's phenotype and family history are highly specific for a disease with single genetic etiology.

A retrospective analysis of 164 patients waiting for surgery for hemangioblastomas at Freiburg University Medical Center, Freiburg, Germany was conducted. Bidirectional direct sequencing by use of an ABI PRISM 3130 DNA Genetic Analyzer (Applied Biosystems) was used to identify mutations in abnormal samples. Patient #3 (male, 47Y) was found to carry the germline VHL nonsense mutation c.481C>T, p.Arg161* (stated as c.694C>T in the paper which used the Latif sequence as reference) and presented with brainstem hemangioblastoma. Family history was not described. ACMG: PP4, PM1

PatientID: 3

KindredID: 3

Case: M, 47Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 38

KindredID: 38

Case: M, 22Y0M, Korean

DiseaseAssertion: VHL

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

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

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

CaseHPOFreeText: Multiple or bilateral retinal hemangioblastomas. Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

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; stop_gained

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

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 4

Case: M, 67Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL mutation - Patient and their 4 relatives harbored p.Arg161X mutation - all with the same phenotypes hemangioblastoma, renal cell carcinoma and pancreatic cysts

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

CaseHPOFreeText: With an age of diagnosis of VHL at 67

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patients with clinical manifestations suggestive of VHL or MEN2 were first screened for VHL or RET mutation, respectively. Possible screening of RET, SDHB and SDHD as well

PreviouslyPublished: N/A

SupplementalData: Yes

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: 5

KindredID: 4

Case: M, 39Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL mutation - Patient and their 4 relatives harbored p.Arg161X mutation - all with the same phenotypes hemangioblastoma, renal cell carcinoma and pancreatic cysts

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

CaseHPOFreeText: With an age of diagnosis of VHL at 39

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patients with clinical manifestations suggestive of VHL or MEN2 were first screened for VHL or RET mutation, respectively. Possible screening of RET, SDHB and SDHD as well

PreviouslyPublished: N/A

SupplementalData: Yes

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

A retrospective medical chart review was performed on patients referred to the genetics service. Four related and one unrelated probands were genetically confirmed with a familial mutation at (presumed) c.481C>T of the VHL gene. The first was a 41 year old female who presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. The second was a 39 year old male who presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. The third was a 67 year old male who presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. The fourth was a 32 year old male who presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. The fifth was a 29 year old female who presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. Family histories are all positive.

PatientID: 4

KindredID: 4

Case: F, 41Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL mutation - This one index case and their 4 relatives harbored p.Arg161X mutation - all with the same phenotypes hemangioblastoma, renal cell carcinoma and pancreatic cysts

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

CaseHPOFreeText: With an age of diagnosis of VHL at 41

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patients with clinical manifestations suggestive of VHL or MEN2 were first screened for VHL or RET mutation, respectively. Possible screening of RET, SDHB and SDHD as well

PreviouslyPublished: N/A

SupplementalData: Yes

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 32

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 32

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0000107; HP:0005584; HP:0009715 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cyst, renal cell carcinoma, papillary cystadenoma of the epididymis)

GroupHPOFreeText:  1 patient has retinal angiomas (retinal capillary hemangioma), 2 have CNS hemangioblastoma, 1 has renal cysts and renal cell carcinoma (RCC), 1 has pancreatic cysts, and one has cystadenomas of the epididymis (papillary cystadenoma of the epididymis).

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

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. The R161 (c.481C>T) mutation was detected in the patient, referred to in the paper by R161 (c.694C>T) due to a difference in transcript sequence. This nonsense mutation was found in 2 unrelated, German families. One VHL type 1 family of 2 affected individuals had one patient with retinal angiomas, 2 with hemangioblastomas of the central nervous system, one with renal cell carcinoma and renal cysts, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 32). Another VHL type 1 family of 3 affected individuals had 3 patients with retinal angiomas, one with hemangioblastomas of the central nervous system, 2 with renal cysts and renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 49). ACMG codes as follows: A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). HPO terms: papillary cystadenomas of the broad ligament.

Seventeen patients (age range 3–73) with VHL, including 12 probands and 5 relatives, that were observed between 2005 and 2020 were recruited for a retrospective analysis in relation to pancreatic neuroendocrine tumors (PanNETs). A total of 13/17 patients had PanNETs. In 4 patients, PanNETs were found at VHL diagnosis and in 9 patients they were found during follow-up after a median time of 12 years. Six of these patients underwent surgery and seven were conservatively treated. Four of these patients had lymph node metastases and a tumordiameter significantly larger than the nonmetastatic PanNETs. Five patients who underwent surgery had stable disease after a 3 year follow up, while one patient showed liver metastases. Similarly, six non-resected PanNETs were stable after a 2 year, while one patient developed a novel small PanNET and slight growth of the pre-existing PanNET. Genomic DNA from blood was extracted and high-coverage sequencing for VHL gene was performed using an AmpliSeq custom panel that targets all exons, as well as intron–exon junctions of genes that are frequently mutated in PanNETs (VHL; RET; MEN1). A total of nine different VHL mutations were identified. Three patients were found to be de novo, but authors did not specify who. This proband (Patient 9) presenting with Renal Cell Carcinoma, pancreatic cyst, kidney cyst and no PanNET was found to have a germline nonsense variant R161*(c.481C>T) in exon 3 of the VHL gene.

PatientID: 9

KindredID: 7

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584; HP:0001737; HP:0000107 (Renal cell carcinoma; pancreatic cyst; renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

PatientID: V-PH-35T

KindredID: 6

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: A family history of VHL associated phenotypes was given. This patient is said to be the sibling of V-PH-34T with the germline VHL mutations: p.Arg161 ; p.Arg200Glyfs2

CasePresentingHPOs: HP:0006748; HP0010797 (adrenal pheochromocytoma, hemangioblastoma)

CaseHPOFreeText: diagnosed with right adrenal phaeochromocytoma at age 39Y, surgery the same year. He also had a personal history including hemangioblastomas, and hypertension.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHA, SDHB, SDHC, TMEM127

PreviouslyPublished: Likely; 26796762 (ID: RNSH09)

SupplementalData: Yes (see table S1 and S10)

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Patient given as ENSP00000256474.2:p.Arg161Ter

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: V-PH-34T

KindredID: 6

Case: M, 40Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: A family history of VHL associated phenotypes was given. This patient is said to be the sibling of V-PH-33T with the germline VHL mutation: p.W117S (c.350G>C). V-PH-35T is also said to be a sibling, with the VHL mutation p.Arg161Ter.

CasePresentingHPOs: HP:0006748; HP0010797; HP:0100565 (adrenal pheochromocytoma, hemangioblastoma, hydromyelia)

CaseHPOFreeText: diagnosed with left adrenal phaeochromocytoma at age 40Y, surgery the same year. He also had a personal history including recurrent pheaochromocytoma and hemangioblastomas, and hydromyelia. He also had raised noradrenaline and normetanephrine levels

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHA, SDHB, SDHC, TMEM127

PreviouslyPublished: Likely; 26796762 (ID: RNSH10)

SupplementalData: Yes (see table S1 and S10)

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Patient given as ENSP00000256474.2:p.Arg161Ter/ENSP00000256474.2:p.Arg200GlyfsTer2

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: CivicName: R161* (c.481C>T) AND R200fs (c.598del)

MultipleGeneVariants: Germline, KIF1B, c.184-6_184-5del; Germline, KIF1B, c.608+8dup; Somatic, VHL, c.delC; Germline, VHL, c.598del (p.Arg200GlyfsTer2)

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

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. Blood samples were taken and analyzed by PCR and single-strand conformational polymorphism (SSCP). VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Group 20, consisted of a proband with retinal capillary hemangioma and a relative who also harboured the germline VHL mutation, R161 (c.481C>T). Group 21, consisted of one proband with retinal capillary hemangioma who also had the R161 mutation. It should be noted that this VHL mutation was stated as c.694C>T in the paper which used the Latif sequence as reference. No other affected family members were described for group 21. Other VHL lesions harbored by the patients were not specified.

PatientID: 1

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history.

CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

CasePresentingHPOs: HP:0006748, HP:0010797, HP:0005584, HP:0009715, HP:0030405 (adrenal pheochromocytoma, hemangioblastoma, renal cell carcinoma, papillary cystadenoma of the epididymis, pancreatic endocrine tumour)

CaseHPOFreeText: The patient had a left adrenal pheochromocytoma at age 42.

CaseNotHPOs: HP:0008221 (Adrenal hyperplasia)

CaseNotHPOFreeText: The patient did not have adrenomedullary hyperplasia.

CasePreviousTesting: N/A

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

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.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

PatientID: 4

KindredID: 4

Case: M, 46Y0M, Bulgarian

DiseaseAssertion: VHL

FamilyInfo: Several family members were affected by the VHL disease: the patient's father has been operated for multiple large cHBs; the patient's brother has been operated for multiple cHBs and died from RCC; his nephew (brother's son) has been operated for large cHB. No familial genotype was confirmed.

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

CaseHPOFreeText: 2 RCC and 2 cHB were both self-reported; patient was operated and treated for RCC; follow-up for cHB.

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: 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: SNP c.870A>G in CCND1 gene (G>G)

75 individuals pre-diagnosed with pheochromocytoma and/or paraganglioma were referred for molecular genetic testing. Genomic DNA of each participant was isolated from peripheral blood samples to look for germline mutations in pheochromocytoma and paraganglioma targeted susceptibility genes. 6 targeted genes (IF1B, RET, SDHB, SDHD, TMEM127, and VHL) were sequenced and identified variants were confirmed by sanger sequencing. Patient 2 was pre-diagnosed with bilateral pheochromocytoma and sequencing identified a germline R161*(c.481C>T) nonsense variant in the VHL gene. Patient 2 had two affected family members, his father and sister. It does not describe how they were affected nor any diagnosis or variant.

PatientID: 63

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S2 describes 9 patients with nonsense mutations, including this patient.

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

LegacyVariant: c.694C>T

CaseProblemVariantFreeText: 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: 61

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S2 describes 9 patients with nonsense mutations, including this patient.

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

LegacyVariant: c.694C>T

CaseProblemVariantFreeText: 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: 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

Of 51 patients tested for VHL mosaic germline mutations, two returned with the c.481C>T (p.Arg161*) variant. The first was a 16 year old male presenting with several retinal haemangioblastomas and renal cysts where his first clinical manifestations presented at 16 years old and it is unknown if this is a familial variant. In this patient, next generation sequencing found 1.7% mutated allele in the blood, ddPCR found 1.9% mutated allele in the blood. The following patient returning positive. He presented with bilateral renal cell carcinoma at age 48 and had a daughter affected by the same heterozygous germline mutation. Next generation sequencing found 1.7% mutated allele in the blood and ddPCR found 1.8% mutated allele in the blood. Both of the patient were diagnosed with clinical VHL. This patient was previously published in 24301059.

PatientID: 25

KindredID: E

Case: Sex Unknown, 32Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: No family history discussed

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

CaseHPOFreeText: Symptomatic by 32Y, clinically manifested as 3 cerebellar hemangioblastomas, pancreatic and renal cyst

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270

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: 28

KindredID: 28

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0100634 (hemangioblastoma, clear cell renal cell carcinoma, neuroendocrine neoplasm)

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

CaseNotHPOs: HP:0030421; HP:0030405; HP:0009711 (epididymal tumour, pancreatic endocrine tumour, retinal capillary hemangioma)

CaseNotHPOFreeText: patient was not recorded to have retinal hemangioblastoma, an epididymal tumor, nor 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.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: 109

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 109

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown or unstated.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

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

PatientID: None

KindredID: 16

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: None

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

CaseHPOFreeText: 3 HB, 1 KC, 1 PC at first and final screenings

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

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

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 were determined from sequencing peripheral blood using PCR, SSCP (single-strand conformation polymorphism), and Southern Blotting. Family 4885 and family 1112 were found with p.Arg161*/c.481C>T mutations in the VHL gene (legacy notation c.694C>T converted to NM_000551.3). Family 4885 had one member with pheochromocytoma, renal cell carcinoma, CNS hemangioblastoma and cysts. Family 1112 had one member with pheochromocytoma, CNS hemangioblastoma, and retinal angioma.

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This nonsense mutation (c.481C>T) was recorded in the paper as c.694C>T due to a difference in transcript sequence. It was found in 4 patients with hemangioblastomas of the central nervous system. Any family information or relations is unknown. No other phenotypes described.

PatientID: 8

KindredID: 8

Case: M,48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: His daughter harboured the same VHL mutation.

CohortInfo:Eight patients whose phenotypes were suggestive of VHL but were negative for a VHL abnormality both by PCR-Sanger sequencing and by quantitative multiplex PCR of short fluorescent fragments (QMPSF).

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: The patient had bilateral renal cell carcinoma at age 48.

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: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 1.7%.

MutationType: stop_gained

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

MultipleGeneVariants: N/A

All hemangioblastoma patients treated at The University of Tokyo Hospital from 1954 to 1998 were retrospectively analyzed. Genetic analysis was done on one 31 year-old male patient (patient #15) using isolated peripheral blood and directly sequenced using BigDye Sequencing Kit and Genetic Analyzer 310 (Applied Biosystems, Foster City, CA). Genetic testing revealed a p.Arg161* nonsense germline mutation in the VHL gene. In this 31-year-old man, CT detected 5 cerebellar hemangioblastomas. Fourteen years later, the patient was found to have another cerebellar lesion. The man had no other lesions detected by scans. The patient had no family history of VHL disease.

PatientID: 6

KindredID: 3

Case: F, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: A family pedigree is provided in figure 1. Both the father and brother of patient 6 were found to have the same mutation. Her father had retinal, cerebellar and spinal hemangioblastomas, as well as retinal detachment. Her 7-year-old brother did not have any known tumours.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: Patient did not have retinal capillary hemangioma or other known tumours.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

Using polymerase chain reaction (PCR)-direct sequencing and universal primer quantitative fluorescent multiplex–PCR, mutations in VHL gene in 19 VHL disease families recruited from the Department of Urology, Peking University First Hospital in the period from 2009 to 2012 were examined. Two probands were found to carry the mutation c.481C>T in exon 3 of the VHL gene leading to an early stop codon. The first proband was from family 14 and presented with hemangioblastoma and renal cell carcinoma at age 29. At age 33, the patient presented with pancreatic cysts or tumours. The patient had positive VHL family history and his father had a hemangioblastoma of the central nervous system at age 42. He was deceased before diagnosis could occur. The other proband was from family 15 and had no VHL family history. The patient presented with hemangioblastoma, renal cell carcinoma, and pancreatic cysts or tumours at age 39. Both of these families were previously published in 29330336.

Nine Chinese index patients were referred for the molecular analysis of VHL based on clinical suspicion. PCR and MLPA were performed on whole blood. One index patient was found to harbor the p.R161* mutation. Clinical manifestations included epididymal cysts, presenting at 40 years of age, and CNS hemangioblastoma and renal cell carcinoma, both presenting at 47 years of age. Familial screening found the mutation present in a sister with renal cell carcinoma (age 45), and absent in 2 asymptomatic daughters.

GroupID: 31

DiseaseAssertion: assumed VHL

GroupSize: 30

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Tissues embedded in paraffin blocks were collected from 203 cHAB patients operated in different Medical Centres in Poland. Eight of these harboured germline mutations in unrelated patients from distinct undiagnosed VHL families. Various variants were unverified as somatic or germline as they were detetced in tumour but blood samples were not tested. Other phenotypes and demographic information is not known. Patient 51 was found with a germline p.Arg161* mutation in the VHL gene with hemangioblastomas.

Thirteen patients with supratentorial hemangioblastoma were studied at Le Kremlin-Bicêtre University. Other phenotypes included: 6 patients with pancreatic cysts, 1 patient with an endocrine pancreatic tumor, 5 patients with renal cell carcinoma, 3 patients with pheochromocytoma, and 6 patients with retina hemangioblastomas, although specific phenotypes for each patient was not described. Blood samples were isolated from patients and the coding sequence and flanking intronic sequences were directly sequenced. Quantitative Southern blotting and multiplex ligation-dependent probe amplification studies were performed to detect large genomic rearrangements. Patient 8 (male) had a germline VHL p.Arg161* mutation. The patient had a meckel cave hemangioblastoma at age 28 and a papillary edema and pituitary stalk hemangioblastoma at age 34.

PatientID: P16

KindredID: P16

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

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:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had a benign pheochromocytoma measuring 50 mm at age 39.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

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: The tumour tested positive for SDHA and SHB IHC.

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: 25Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: No family history

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0000107 (hemangioblastoma; renal cell carcinoma; pancreatic cysts; renal cyst)

CaseHPOFreeText: Aged 25Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS angiomas diagnosed at 22, ccRCC at 22Y, renal cysts and pancreatic cysts at 22Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 2 MA

KindredID: 2

Case: M, 35Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: Patient had two other affected family members: their father and sister. It does not describe how they were affected nor any diagnosis or variant.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

A case report of a 31 year old female patient diagnosed with VHL disease revealed a c.481C>T mutation in the VHL gene, leading to the subsequent protein change Arg161*. Tissue resection was analyzed through DNA amplification. There was no family history of illness. Over an 8 year follow-up period the 31Y old patient presented with bilateral RCC, bilateral renal cysts, cardiomegaly, multiple brain hemangioblastomas, pancreatic neuroendocrine carcinoma, pancreatic cysts, kidney cysts, and ovarian cysts.

A retrospective study reviewed cases of 23 patients with advanced and complicated VHL eye disease who underwent pars plana vitrectomy in the years 1999 to 2012 that were a part of 223 VHL patients consulted at the International Hereditary Cancer Center and Polish VHL Registry. Genetic molecular analysis was performed in 22/23 patients through PCR and MLPA, and 24 eyes from 23 patients were studied. A germline c.481C>T transition was would in 3 individuals, and results in a p.Arg161* protein change and premature stop codon. A 35 year old (Patient 3) had a previous history of HbCNS. Patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery. A 35 year old patient (Patient 7) had a previous history of HbCNS and RCC. The patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery. An 18 year old (Patient 9) had a previous history of HbCNS, ELST, and RCC. Patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery. Since patients were listed 'by eye' it is impossible to determine how many patients listed above actually represent unique patients.

PatientID: None (proband 15)

KindredID: 15

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Father had died before diagnosis therefore no DNA sample available; He presented with CNS hemangioblastomas at the age of 42.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715; HP:0030393 (hemangioblastoma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis, endolymphatic sac tumor)

CaseHPOFreeText: Patient presented with hemangioblastoma at age 29, renal cell carcinoma at age 29, pancreatic cysts at age 36, endolymphatic sac tumor at age 33, papillary cystadenoma of the epididymis at age 29.

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: 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

37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. Parts of the Danish cohort have been previously assesed in the following papers PMID: 19863552, 25834951, 27966541, 27539272. Peripheral blood samples were isolated and sequenced coding exons and exon-intron boundaries using MLPA (Multiplex Ligation-dependent Probe Amplification). One family with one patient (Family ID14) was found with a germline mutation in the VHL gene (R161*; c.481C>T). The patient was diagnosed at 10Y and had 2 epididymal cystadnomas at 10Y. The patient was 46 by the end of the study.

A cohort of 36 PCCs and four functional PGL tumours were analysed by exome-seq and high-density SNP-array analysis using tumor paired blood. This specified germline VHL mutation (tumor ID: V-PH-35T) belonged to a male diagnosed with right adrenal phaeochromocytoma at age 39Y, surgery the same year. He also had a personal history including hemangioblastomas, and hypertension. The VHL mutation R161* (c.481C>T) was present. This patient was said to be the singling of ID: V-PH-35T, who possessed the germline VHL mutations: p.Arg161Ter and p.R200fs (c.598del). Additionally, this patient was likely previously published in PMID: 26796762 (ID: WM02).

A 19-year-old female patient was referred to a psychiatric inpatient service due to a suspicion of anorexia nervosa (AN) following severe weight loss, low food intake, and a lack of a menstrual cycle for at least 1 year. The patient is the second child of a non-consanguineous relationship and there were no abnormalities in developmental milestones, but her weight never exceeded 35 kg. Apart from weight loss and weakness, physical and neurological examinations showed no alterations. The patient frequently complained of epigastric burning sensation, nocturnal headaches, postural hypotension and difficulty swallowing. The patient did not meet the necessary criteria for a diagnosis of AN or another psychiatric disorder. The patient experienced episodes of nausea during fasting after waking up, followed by unprovoked vomiting, which is highly uncommon in AN. Blood tests, urinalysis and chest X-ray were all normal. Abdominal CT scan revealed cystic lesions throughout the parenchymatous portion of the pancreas, suggestive of VHL. After 3 weeks of hospitalization, the patient progressively developed gait abnormality and bilateral dysmetria, which was worse on the left side. A brain MRI examination revealed a massive lesion suggestive of a hemangioblastoma (HB) in the fourth ventricle causing hypertensive hydrocephalus. HB and pancreatic cysts support the diagnosis for VHL. Whole blood was obtained for sanger sequencing of all 3 exons of the VHL gene, revealing a nonsense mutation in the VHL gene (c.481C>T; p.Arg161*) that results in a truncated protein. In silico analyses by mutation analyzer 2.0.28 suggests a pathogenic variant. Surgery inserting a ventriculoperitoneal shunt to relieve the hypertensive hydrocephalus only temporarily relieved her appetite; yet she no longer had fasting nausea and vomiting, or nocturnal headaches. Fractionated radiotherapy did not improve appetite or nausea but was successful in controlling tumor growth as an MRI revealed no significant alterations in the size of the lesion six months post-radiotherapy.

PatientID: N/A (case)

KindredID: 1

Case: F, 19Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Non-consanguineous parental relationship; second child; no mention of VHL in the family.

CasePresentingHPOs: HP:0010797; HP:0001713; HP:0002039; HP:0001824 (Hemangioblastoma; pancreatic cysts; anorexia; weight loss)

CaseHPOFreeText: Healthy from birth, this patient was referred to a psychiatric inpatient at 19Y with the weight loss and weakness, and the suspicion on anorexia nervosa. AN was not met according to the DSM-5 or ICD-10 (despite anorexic tendencies). There were also no tendencies towards an eating disorder. Patient developed progressive gait abnormality, along with bilateral dysmetria. MRI revealed a massive lesion with vascular characteristics suggestive of a HB in the fourth ventricle causing hypertensive hydrocephalus. Abdominal CT scan revealed cystic lesions throughout the parenchymatous portion of the pancreas, suspected to be related to VHLs. Together, supported the diagnosis of VHL. The patient underwent surgery of the brain, and radiotherapy which proved to work in small degrees.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: All blood tests, urinalysis and chest X‑ray were unremarkable. She also had no pheochromocytoma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: stop_gained

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

MultipleGeneVariants: N/A

Of 38 PPGL (pheochromocytoma and paraganglioma) cases studied, three were associated with an individual carrying the germline mutation c.481C>T (ENSP00000256474.2 p.Arg161*) of the VHL gene. This mutation was identified using germline clinical sequencing on formalin-fixed and paraffin-embedded (FFPE) tissue and confirmed with sanger sequencing. The authors identified the reference sequence used as NM_000551.3. The first patient (ID: RNSH06) presented with bilateral adrenal phechromocytoma (34yo), ID: RNSH09 with right adrenal phechromocytoma (39yo), and ID: RNSH10 with left adrenal phechromocytoma (40yo). No family history, or relation, was presented. RNSH09 and RNSH10 were likely previously published in PMID: 25545346.

GroupID/ KindredID: 15

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This mutation (p.R161* (c.481C>T)) was found in Family No. 15 with 1 member affected.

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

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: 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: 1

KindredID: 96

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R167* (c.694C>T)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Loss of heterozygosity

MutationType: stop_gained

CivicName: R167* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: P3

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: HB1 and HB2 were detected in this patient (P3/1)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R167* (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: R167* (c.481C>T)

MultipleGeneVariants: N/A

GroupID: 184

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.481C>T variant causing a Arg161* stop gain (noted in the paper as c.694C>T due to Latif reference transcript being used). It was noted that this family had no history of pheochromocytoma's.

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: It was noted that this family had no history of pheochromocytoma's.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.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

PatientID: 2

KindredID: 2

Case: M, 38Y0M, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0002666; HP:0005584 (Pancreatic cysts; pheochromocytoma; renal cell carcinoma)

CaseHPOFreeText: Pancreatic microcyst adenomas (Pancreatic MCAs), and other VHL disease-associated tumors

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: See Table 2 (case 2) for LOH information

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Through blood sample testing, ten affected individuals from 7 families in Singapore were identified with VHL disease. One patient of Malay ethnicity was found with the c.481C>T (p.Arg161*) mutation in the VHL gene and presented with CNS hemangioblastoma, retinal angioma, renal cell carcinoma, renal cysts, and pancreatic cysts. ACMG: PVS1, PP4

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.R161* (c.481C>T) germline variant of the VHL gene was detected in a family (ID 41). Members 4732 and 1426 had unknown renal involvement. Member 1825 had no renal involvement. Members 1206 and 3600 presented with mild renal disease. Members 4616, 4731, 4446 and 1937 presented with moderate renal disease (RCC). Another family (ID 46) was found with this variant. Member 5024 had unknown renal involvement. Member 5025 had no renal involvement. Another member (no ID provided) presented with mild renal disease (RCC) as well as member 5080. Member 5078 presented with moderate renal disease (RCC). The paper states that these families are previously reported in PMID 12202531 and/or 9829912.

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, the missense mutation (c.481C>T (p.Arg161Ter)) was found in 8 patients total - 3 of which are stated to have retinal HBs and 5 are said to not. Other manifestations are possible but not clear. This is possibly previously published in PMID: 15300849

GroupID: 43

DiseaseAssertion: VHL

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

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

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

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

GroupNotHPOs: N/A

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

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Of 14 patients with retinal vascular proliferation and known family history of VHL disease, 12 patients were enrolled in an approved study protocol at the National Cancer Institute. 11 of these patients underwent genetic testing and were found to have mutations in the VHL gene. Patient 8 was a 29-year-old white woman with a history of poor vision in her left eye from age 5 years. At that time, no typical RCHs were found but she was noted to have a large peripapillary fibrovascular complex in her left eye that extended into the macula. No treatment was rendered. At age 29 years, visual acuity was 20/500 OS. On examination, a papillary fibrovascular stalk could be seen extending from the nerve into the vitreous and also onto the center of the macula, exerting tractional effects on retinal vessels in the major vascular arcades. Areas of chronic pigmentary change were also present in the macula. No vascular lesions were observed in the right eye. At the last checkup, patient 8 had retinal vascular proliferation, pancreatic and CNS abnormalities, and endolymphatic sac tumor. She had the R161* (c.481C>T) VHL mutation. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

A retrospective study described polyglobulia in 19 patients precise germline VHL mutations and with hemangioblastomas. 10 other patients followed with VHL mutations without an exact location. Patient 17 was a 47Y male with raised hemoglobin levels. They had a hemangioblastoma tumor 5.3cm3 in size. The mutation p.R161* (c.481C>T) was described in the paper as c.694C>T due to a difference in transcript reference. No family information was provided.

PatientID: 17

KindredID: 17

Case: M, 47Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: No details on family information.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.694C>T

CaseProblemVariantFreeText: 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: II/1

KindredID: 1

Case: F, 33Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: A patient was found to have a mutation in the VHL gene (R161* (c.481C>T)), this patients parents were tested for the same mutation in VHL, but testing revealed no VHL gene mutation. Pedigree: see Figure 1.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: developed cerebellar hemangioblastoma at age 33

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: R161X (8684C>T)

ClinVar: 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

The proband (II/1), of Italian descent, was found to have the c.481C>T change (referred to in the paper as 8684 C->T due to a difference in transcript sequence) causing a p.R161* mutation in the VHL gene. This variant was detected using direct sequencing of PCR products obtained from genomic DNA extracted from the patients peripheral blood leukocytes using the DNA extractor BIO ROBOT EZ 1 (Qiagen). Genetic testing revealed that her parents did not have the VHL gene mutation. She presented with a cerebellar hemangioblastoma at age 33. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

GroupID/ KindredID: F9

Case: Sex unknown, 20Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: None. Microsatellites were used to exclude nonpaternity, and the de novo character of the mutation was demonstrated in this patient. Paper says its confirmed however only discuss nonpaternity.

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

CaseHPOFreeText: Cerebellar hemangioblastoma was found with multiple lesions. Age of onset is 20Y0M.

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: 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

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. This nonsense mutation, c.481C>T, was found in 3 VHL patients. The 17-year-old VHL patient only had hemangioblastomas of the central nervous system (CNS) (index case 218). The 24-year-old VHL patient had CNS hemangioblastomas and clear cell renal cell carcinoma (index case 46). The 29-year-old VHL patient had CNS and retinal capillary hemangioma and pheochromocytoma (index case 79). ACMG code as follows: There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease.

PatientID: 218

KindredID: 218

Case: Sex Unknown, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0010797 (hemangioblastoma )

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0001737, HP:0002666, HP:0000107, HP:0006770 (retinal capillary hemangioma, pancreatic cyst, pheochromocytoma, renal cyst, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France).No variants were found in 96 control cases. This stop gain mutation, c.481C>T, was found in 2 unrelated VHL type 1 patients (patient V3, V46). No patient information was provided and no additional family members were screened. Patient V3 was previously published in 8956040.

PatientID: V3

KindredID: V3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8956040

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

KindredID: 4885

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The patient was also described to have cysts but the type or location was not specified.

CaseNotHPOs: HP:0009711; HP:0030405 (Retinal capillary hemangioma, Pancreatic endocrine tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 694, C to T (Arg to stop), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.481C>T, p.Arg161* (NM_000551.3).

MutationType: stop_gained; missense_variant;transition

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

MultipleGeneVariants: N/A

KindredID: 1112

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0030405; HP:0005584 (Pancreatic endocrine tumor, Renal cell carcinoma)

CaseNotHPOFreeText: The patient had no cysts (type or location was not specified).

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 694, C to T (Arg to stop), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.481C>T, p.Arg161* (NM_000551.3).

MutationType: stop_gained; missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: 51

KindredID: 51

Case: Age, sex, ethnicity unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

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: 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: 8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Her father harboured the same VHL mutation and presented with bilateral renal cell carcinoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient had bilateral renal cell carcinoma at age 48.

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: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: She had a heterozygous p.R161* mutation.

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: B

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The parents of the patient rejected clinical and genetic screening, whereas clinical screening in a younger brother of the index patient revealed no abnormality.

CasePresentingHPOs: HP:0009711, HP:0000107, HP:0001737, HP:0001901, HP:0006880 (retinal capillary hemangioma, renal cyst, pancreatic cysts, polycythemia, cerebellar hemangioblastoma)

CaseHPOFreeText: Retina involvement presented at age 19. The patient had cerebellar hemangioma as well as renal and pancreatic cysts at the age of 27 years.

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

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

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: 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: 31

KindredID: 22

Case: Sex Unknown, 32Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: stated as a familial VHL. 1 other family member (patient 30) with that same mutation was stated with an age of 56. This patient has RCC, renal cysts, pancreatic cysts, and CNS hemangioblastoma and retinal capillary hemangioblastomas.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584; HP:0000107 (hemangioblastoma, pancreatic cyst, renal cell carcinoma, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668, HP:0002666; HP:0009711; HP:0030405; (Paraganglioma, pheochromocytoma, retinal capillary hemangioma, pancreatic endocrine tumor)

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

GroupID: 13

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 2 patients with a R161* (c.481C>T) 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.R161* (c.481C>T)

LegacyVariant: N/A

GroupProblemVariantFreeText: 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