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: 1347

KindredID: 363

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 12202531

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

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

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.N78S (c.233A>G) germline variant of the VHL gene was detected in two individuals (ID 1347/Family 363 and ID 9579/Family 404). Both patients presented with renal cell carcinoma. No family information is provided. Both individuals were previously published in PMID 12202531.

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. Genotyping confirmation was performed by PCR-direct sequencing on peripheral blood samples. Three individuals (one proband and two family members) were genetically confirmed to have the p.N78S(c.233A>G) familial mutation. The proband (patient #36) was a male from kindred (family) #12 who was diagnosed with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at the age of 34. His sister (patient #37) also possessed this germline mutation and presented with multiple pancreatic cysts/tumors at age 27. The proband's father (patient #38) also had this mutation and presented with renal cell carcinoma at age 55. A fourth individual, the proband's uncle, passed away before diagnosis. He presented with a CNS hemangioblastoma at age 19, but was not genetically confirmed to have the mutation. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: II-5

GroupID/ KindredID: 6

Case: Age unknown (deceased), M, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: No VHL gene test was conducted but due to substantial family pedigree history, can assumed with confidence this mutation

LegacyVariant: p.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: III-9

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: III-14

GroupID/ KindredID: 6

Case: 46Y0M, F, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: HP:0001732; HP:0005584; HP:0002666 (abnormality of the pancreas, Renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: CT of the abdomen demonstrates a cystic lesion in right adrenal and a solid tumor in right kidney. Pathological results confirm pheochromocytoma and clear cell carcinaoma

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 6 was found with p.Asn78Ser mutation in the VHL gene: 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. 10/18 members had CNS hemangioblastoma, 5/18 had retinal angioma, 12/18 had RCC, 7/18 members had a pancreatic lesion, and 1/18 had pheochromocytoma. ACMG PP4

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: None

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The four patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

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 de novo, missense mutation, c.233A>G, was found in 2 VHL patients. A 24-year-old patient had retinal capillary hemangioma, pancreatic lesions, and renal cysts (index case 152). The other patient, a 33-year-old, presented with hemangioblastomas of the central nervous system and pancreatic lesions (index case 45). This variant also potentially alters the stability of the beta domain of the VHL protein. There is strong evidence for pathogenicity because this variant is de novo in a patient with the disease and no family history.

GroupID: II (from Hemangioma VHL Associated Group)

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Studied 36 VHL-related pheochromocytoma by comparative genomic hybridization. In addition, we compared their genetic profiles with those of (1) multiple endocrine neoplasia type 2 (MEN 2)-related pheochromocytomas; (2) previously reported sporadic pheochromocytomas; and (3) VHL-related CNS hemangioblastomas.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had two VHL associated hemangioblastomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1 and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

The National Cancer Institute has a frozen tumour bank of ccRCC tumours that have been removed from VHL patients. Illumina's Human Whole-Genome Sequencing service was used to sequence blood, tumour tissue, and normal kidney tissue. One 28Y male patient with ccRCC was confirmed with a germline missense mutation (p.Asn78Ser) in the VHL gene. No family history or other phenotype was provided.

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There was 1 patient reported with the c.233A>G (p.N78S) mutation. This member presented with retinal hemangiomas. No family information was provided.

In a study from the National Cancer Institute, 6 unrelated VHL patients with known germline VHL mutations underwent surgery for uni- or bilateral renal lesions. The paper used legacy notation for VHL point mutations, so mutations were converted and reported in VHL NM_ 000551.3. DNA was prepared from either cells in culture (grown from renal lesions) or primary formalin- or ethanol-fixed tumor lysates under salt-free conditions.Patient #4 was 27Y female (current age at time of study) with a germline VHL missense mutation (c.233A>G, originally written in the paper as legacy notation c.446A>G) and presented with CNS hemangioblastoma, renal cell carcinoma, renal cysts, pancreas lesion, and adrenal lesion. Family history was not described.

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 2a) with Renal Cell Carcinoma, CNS/Retinal Hemangioblastoma, Pancreatic cysts, and PanNET was found to have a germline missense variant N78S(c.233A>G) in exon 1 of the VHL gene. A relative (Patient 2b) was found to carry the same mutation with the same clinical presentation, except with additional Paraganglioma.

Of 31 Brazilian patients, one was found to harbour the c.233A>G (p.Asn78Ser) mutation of the VHL gene. Genomic DNA was extracted and all VHL coding regions were analyzed by Sanger sequencing. MLPA was performed to investigate large deletions using SALSA® MLPA® P016 VHL probe mix. Data analysis was performed with Genescan 3.7. This patient, age 33, presented with a paraganglioma, pheochromocytoma, pancreatic endocrine tumor, renal cell carcinoma, renal cyst, pancreatic cyst and a CNS hemangioblastoma. It is not clear if this mutation is familial. ACMG evidence codes: 'PP4' since the patients present phenotypes highly specific for a disease with a single genetic etiology.

PatientID: VHL-11

KindredID: 11

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

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

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

CaseHPOFreeText: The patient had multiple hemangioblastomas.

CaseNotHPOs: HP:0005584, HP:0001737, HP:0002666 (renal cell carcinoma, pancreatic cysts, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: F1-II-3

KindredID: 1

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patients brother (F1-II-1) was a 31-year old male patient with pheochromocytoma, renal cell carcinoma, and epididymal papillary adenoma. The patients nephew (F1-III-1) was a 5 year old male with no clinical presentation, yet had the same VHL mutation.

CasePresentingHPOs: HP:0005584, HP:0030421, HP:0001737 (renal cell carcinoma, epididymal neoplasm, pancreatic cysts)

CaseHPOFreeText: presented with multiple right renal masses, epididymal nodules and multiple pancreatic cysts

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: CA020131

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

Direct sequencing and multiplex ligation dependent probe amplification were performed on thirteen unrelated subjects with VHL mutations. The clinical manifestations and family histories of the subjects were evaluated. A 14 year old Korean male patient presented with central nervous system hemangioblastoma, retinal hemangioblastoma, multiple pancreatic lesions, and bilateral renal cysts. Genetic testing confirmed a non-familial missense mutation at c.233A > G of the VHL gene. The patient had no family history of VHL.

PatientID: 2

KindredID: 2

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0009711; HP:0001737; HP:0006770 (Renal neoplasm, Multiple renal cysts, Retinal capillary hemangioma, Pancreatic cysts, Clear cell renal cell carcinoma)

CaseHPOFreeText: Patient 2 was a 44-year-old female with a medical history of asynchronous bilateral solid renal tumors some which were further characterized as clear cell RCC, multiple renal cysts, retinal angioma, pancreatic cysts.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.446A>G

CaseProblemVariantFreeText: N/A

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

CAID: CA351749194

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S (c.223A>G)

MultipleGeneVariants: N/A

PatientID: II-2

GroupID/ KindredID: 6

Case: Age unknown (deceased), M, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: No VHL gene test was conducted but due to substantial family pedigree history, can assumed with confidence this mutation

LegacyVariant: p.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

Two VHL syndrome pedigrees were investigated in this study; family 1 was a three-generation pedigree including 6 individuals. In family 1, the proband (F1-II-1), a 31-year-old male patient, presented with headache, paroxysmal hypertension and dizzy spells in 2009 with a 4-year history. Ultrasound and MRI scans confirmed single masses, multiple tumors and multiple cysts in the right adrenal glands, bilateral kidney and pancreas, respectively. Right pheochromocytoma and multiple right renal cell carcinoma were confirmed by histopathological examination. In 2012, the patient was diagnosed with bilateral epididymal head multiple nodules. Bilateral epididymal tubercle resection was performed and epididymal papillary adenoma was confirmed by histopathological examination. Additionally, the patient's younger brother (F1-II-3, 30 years old) presented with multiple right renal masses, epididymal nodules and multiple pancreatic cysts. Radical right nephrectomy was performed and histopathological analysis revealed right RCC with hemorrhagic cyst. In family 1 they identified a heterozygous variant, c.233A>G (p.N78S), within exon 1 of the VHL gene in two affected cases and one clinically normal family member (F1-III-1, the proband's 5-year-old son). Peripheral blood samples were collected for mutation analysis of the RET proto-oncogene and VHL tumor suppressor gene. PCR amplification of all exons and the flanking splice junctions of RET and VHL was performed, followed by direct bidirectional DNA sequencing. One hundred unrelated controls with a similar ethnic background were also included in this study. ACMG evidence codes: ‘PP4’ because the family history is highly specific for a disease with a single genetic etiology, ‘PP1’ because there is co-segregation of the variant with VHL disease in the family.

PatientID: proband (F1-II-1)

KindredID: 1

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This proband had a 5-year-old asymptomatic son who carried the same mutation. The proband's brother (F1-II-3) was a 30 year-old who presented with multiple right renal masses, epididymal nodules and multiple pancreatic cysts. Histopathological analysis revealed right renal cell carcinoma with hemorrhagic cyst

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

CaseHPOFreeText: Ultrasound (US) and magnetic resonance imaging (MRI) scans confirmed single masses, multiple tumors and multiple cysts in the right adrenal glands, bilateral kidney and pancreas, respectively. Right pheochromocytoma and multiple right renal cell carcinomas were confirmed by histopathological examination. In 2012, the patient was diagnosed with bilateral epididymal head multiple nodules. Bilateral epididymal tubercle resection was performed and epididymal papillary adenoma was confirmed by histopathological examination.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: CA020131

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Peripheral blood leukocytes were isolated and directly sequenced using the BigDye Terminator Cycle Sequencing Ready Reaction kit on an ABI Prism 3130 genetic analyzer (Applied Biosystems). One 34Y male patient (Patient 15) presented with multiple and/or bilateral RCC and a CNS hemangioblastoma. He had a germline missense mutation in the VHL gene (c.233A>G p.Asn 78 Ser). The patient had a negative family history of VHL disease. The phenotypes of this patient were revised from a previous report in PMID 19270817 and/or 19949673.

PatientID: 15

KindredID: 15

Case: M, 34Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None.

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

CasePresentingHPOs: HP:0010797, HP:0005584 (Hemangioblastoma, renal cell carcinoma )

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19949673

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: 152

KindredID: 152

Case: Sex Unknown, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0010797, HP:0006770 (pheochromocytoma, hemangioblastoma, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

PatientID: 45

KindredID: 45

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 51

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A