A case report of a female patient with cereballar hemangioblastoma at 23Y and endolympathic sac tumour repeating at 23Y and 25Y revealed a mutation c.194C>T in the VHL gene. The mutation was found in both the hemangioblastoma and and the ELST, as well as in the patient's father, concluding germline origin. The patient's father had cerebellar hemangioblastoma at age 30, and bilateral renal cell carcinoma. He died at 43Y due complications from metatasized RCC. The patient's grandfather and uncle also had VHL-like multi-tumours, but genetic confirmation was not determined and symptoms were not specified. Cosegregation with disease and multiple affected family members may be supportive of PP1. Patients' phenotypes are highly specific to VHL disease (PP4).

PatientID: VH7

KindredID: F3

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: Family history of pheo (type 2 VHL with no other lesions). Two other family members are given: VH5, 25Y Female, and VH6, 54Y Male both with an isolated pheochromocytoma too.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24735130

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R82L (c.245G>T)

MultipleGeneVariants: N/A

PatientID: 24

KindredID: 4

Case: M, 14Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: 14Y at VHL diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

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 31 was a 32Y male with raised EPO levels. They had a hemangioblastoma tumor 0.2cm3 in size. The mutation p.P81S (c.241C>T) was described in the paper as c.454C>T due to a difference in transcript reference. No family information was provided.

PatientID: 1 (case)

KindredID: 1

Case: F, 12Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Family history revealed that her mother had had bilateral partial adrenalectomy for pheochromocytoma during her youth; more recent follow-up investigations of the patient’s mother also revealed cerebral hemangioblastomas and a neuroendocrine tumor of the pancreatic head with liver metastases. She also showed the same mutation upon further follow-up.

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

CaseHPOFreeText: Patient was affected for 1 year prior diagnosis by intermittent epigastric pains and diarrhea (clinical workup revealed a pancreatic tumor). Patient also showed a bilateral adrenal enlargement (pheochromocytoma - (11 mm right and 17 mm left)). There was no evidence of infiltration of the vena mesenterica superior. The mesentericoportal venous trunk and the large arterial vessels of the epigastrium were dissected from the tumor and preserved.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

Through peripheral blood sequencing and PCR/MLPA, 5 Bulgarian patients and their families underwent molecular genetic testing for clinically suspected VHL. 4 family members were documented and were confirmed with a c.481C>T (p.Arg161*) germline mutation in the VHL gene. A 46Y male patient presented with two RCCs and two CNS hemangioblastomas, self-reported. The patient had a positive family history of VHL: patient’s father has been operated for multiple large CNS HBs; the patient’s brother has been operated for multiple CNS HBs and died from RCC; his nephew (brother’s son) has been operated for large CNS HB. No familial genotype was confirmed beyond the individual patient (ID: 4).

PatientID: 22

KindredID: 22

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880; HP:0005584 (Cerebellar hemangioblastoma, Renal cell carcinoma)

CaseHPOFreeText: Cerebellum hemangioblastoma and RCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.475T>A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Preoperative hemoglobin: 15.2. No postoperative follow-up.

MutationType: missense_variant;transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

This case study focused on a 64-year-old man who was admitted for abdominal pain and was found to have a solid tumor with areas of necrosis in the upper pole of the left kidney, clear cell renal cell carcinoma, and adenocarcinoma of the colon. At age 69, he was found to have an adrenal pheochromocytoma in the right adrenal gland, multiple cysts in the right kidney and liver. At age 73, several metastatic sites were found in the lungs, lesions at the mediastinum, and right sovraclaveare lymphadenopathy. An angobiopsy revealed clear cell renal cell carcinoma in these cells. Later in the year imaging revealed progression of pulmonary disease. At age 74, he presented with multiple hepatic metastases and worsening of the mediastinal adenopathy and pulmonary metastases. At age 75 he was admitted for pulmonary edema and died a few days later. The patient underwent genetic testing using PCR-SSCP sequencing and was found to harbour the c.74C>T mutation in exon 1 of the VHL gene. His brother was also found to have this mutation but he was asymptomatic. A pedigree is provided but it is unclear as to whether the rest of the family underwent genetic sequencing.

PatientID: 4 AGY

KindredID: 4

Case: M, 29Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient's mother was an affected family member described (no mutation or phenotypes detailed). Additionally his brother (case 5) had the same mutation with pheochromocytoma and right ccRCC.

CasePresentingHPOs: HP:0002666; HP:0001737 (Pheochromocytoma; Pancreatic cysts)

CaseHPOFreeText: Patient had bilateral renal and eyes pheochromocytoma, with pancreatic cysts

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S68P (c.202T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621912 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.202T>C

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S68P (c.202T>C)

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. One proband (family 6) was found to carry the mutation c.349T>G in exon 2 of the VHL gene. The proband presented with presented with hemangioblastoma at age 36. At age 40 he/she presented with pancreatic cysts or tumours. At age 44 the patient had retinal angioma, renal cell carcinoma, and epididymal or ovarian cystadenoma. The patient had a strong family history of VHL. Patient's son who was confirmed to have this mutation presented with hemangioblastoma at age 12. The patient's mother, aunt, grandmother, brother 1 and 2, and sister 3 all passed before they could undergo genetic testing but had a variety of VHL presentations. The patient's first sister and third nephew were confirmed to have this genetic mutation. The first sister presented with abnormality of the pancreas at age 53. The nephew had hemangioblastoma and retinal angioma at age 13. This family was previously published in 29330336.

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 6 patients were found to have the above mutation (c.464-2A>G). 2 were VHL patients with ICTs (pancreatic neuroendocrine tumors) taken from the VHL-registry. The other 4 patients were stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

GroupID: 12B

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET- Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: HP:0030405 (pancreatic endocrine tumor)

CasePreviousTesting: Patient was negatively tested for islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A122I (c.364_365delinsAT)

LegacyVariant: N/A

CaseProblemVariantFreeText: Authors report this as: c.364_365GC>AT; which can be translated to c.364_365delinsAT

ClinVarID: N/A

CAID: CA658820874 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.364_365delinsAT

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName: A122I (c.364_365delinsAT)

MultipleGeneVariants: N/A

PatientID: 140

KindredID: None

Case: Age and Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; See Suppl 1 (Supporting table)

Variant: c.341-?-463+?del

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: c.341-?-463+?del

MultipleGeneVariants: N/A

This missense mutation was found in a Japanese family with 2 carriers. One Japanese male patient was found with a retinal hemangioma in the left eye at 11 years old and underwent laser surgery. At 29 years old, he was diagnosed with an intracranial hemangioblastoma, a left renal tumor, and bilateral adrenal pheochromocytomas. His brother, mother, and 2 daughters (1 and 5 years old) were asymptomatic. Peripheral blood was isolated and amplified using PCR and subsequently directly sequenced using a dye terminator sequencing kit. The sequencing reaction products were electrophoresed on a genetic analyzer and analyzed using sequence analysis software (ABI PRISM 310; Perkin Elmer Applied Biosystems, Foster City, CA, USA). Genetic testing on the 4 family members revealed that the patient and his 5-year-old asymptomatic daughter harbored the c.500G>A mutation leading to an amino acid change at protein position 167 (stated as 713G>A causing a mutation in codon 238 in the paper which used the Latif sequence as reference). The patient's father died suddenly at 63 years old of an unknown cause.

The authors described the growth kinetics of 96 renal tumours in 64 VHL patients (32 males, 32 females). All patients had VHL disease with renal involvement. 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 patients, at least one or more RCC was 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. 10-ml EDTA anticoagulated blood samples were available from each patient for mutation screening of all exons of the VHL gene. Genomic DNA from blood samples was extracted using standard methods. Small deletions/insertions or point mutations were identified by DNA sequencing followed by complete mutation screening using PCR/single-strand conformation polymorphism and denaturing high-performance liquid chromatography. A germline deletion p.E160Afs*13(c.479_480delAG) was identified in patient #58. This mutation was noted as c.691-92delAG in the paper due to a difference in reference transcript used (see Table S5). No family information is available for this patient.

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

NM_000551.3

GenotypingMethod: PCR amplification was performed searching for point mutation in the entire VHL coding sequence and promoter region, including exon-intron boundaries. Amplification was performed in a Gene Amp PCR System 9700 (Perkin Elmer).

SamplingMethod: When mutations were detected in DNA from tumor samples, it was searched for in the corresponding peripheral blood DNA in order to identify germline mutations.

PatientID: III-4

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: Assumed VHL (Asymptomatic)

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Deceased.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Mutation not confirmed. Authors assume variant.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: V-31

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

KindredID:25

GroupID:5

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.25 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.407C>G (p.S136W)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence:

MutationType: missense_variant;transversion

CivicName: S65W(c.194C>G)

MultipleGeneVariants: N/A

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The c.481C>T (p.R161) stop-gain mutation (noted as c.694C>T (p.R232) in the paper due to a difference in reference transcript used) was found in at least one patient in 3 kindreds (families): kindred no.s 90, 92, and 105. No phenotypic information is reported for kindred no.s 90 and 105. Pheochromocytoma was not observed in any members of kindred no. 92 (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper. ACMG evidence codes: none.

PatientID: N/A

KindredID: 3

Case: Sex Unknown, 17Y0M, Ethnicity Unknown

DiseaseAssertion: Renal Cyst

FamilyInfo: This patient (a relative of patient B3) had two first degree relatives who were positive for the VHL mutation. The first family member (patient B3) had a cerebellar hemangioblastoma at 40 and a pheochromocytoma at 41 years old and the second family member had a hemangioblastoma and retinal angioma at 18 years old

CasePresentingHPOs: HP:0000107 (renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167Q (c.713G>A)

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (F119L (c.357C>G)) was taken from the National Cancer Institute database, with an unknown number of members belonging to two family IDs: Family ID 4414NCI and 4577NCI. It was reported in the paper as c.570C>G due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (N150fs (c.449delA)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3575NCI. It was reported in the paper as c.661delA due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (S183* (c.548C>A)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 6CE. It was reported in the paper as c.761C>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 2547NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 2547NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

LegacyVariant: p.G93D (c.491G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 496054 https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

PatientID: II.2

KindredID: F10

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: This patient’s sibling and both parents were all carriers of the D143= (c.429C>T) germline VHL variant. Their brother was diagnosed with splenomegaly and polycythemia and was homozygous for the variant. All other family members were asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D143= (c.429C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 416990, https://www.ncbi.nlm.nih.gov/clinvar/variation/416990/

CAID: N/A

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/3-10188286-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition; synonymous_variant

CivicName: D143= (c.429C>T)

MultipleGeneVariants: N/A

The VHL gene was analyzed in 3 families from a Serbian population. Genomic DNA was screened by SSCP analysis and patients with variant bands were subjected to sequencing and confirmatory re-sequencing. Family A members AI1, AII2, AII6, AIII3, AIII4, AIII5, AIII6, AIII7, AIII8, and AIII9 were screened by SSCP analyses. There were four symptomatic patients in family A, two (AII2; AIII3) of which were found to have a missense G93C (c.277G>T) variant in VHL, reported in the paper as G93C (c.490G>T) due to a difference in transcript sequence, while the other two affected family members (AI1;II5) were not genetically tested. Patient AI2 was female and had CNS hemangioblastoma. Two of her daughters, patient AII2 and AII3 were found with VHL lesions. Patient AII2 was diagnosed at 33Y pheochromocytoma and patient AII3 had pheochromocytoma with CNS hemangioblastoma (age unknown). Patient AII2's son, patient AIII3, had hypertension since 12Y and was diagnosed and operated for pheochromocytoma at 24Y.

PatientID: proband 17

KindredID: 17

Case: M, 21Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: the patients mother was found at 43Y with RCC and multiple pancreatic cysts or tumors, however she passed before any diagnosis of DNA sample was provided

CasePresentingHPOs: HP:0009711; HP:0009715 (retinal capillary hemangioma, Papillary cystadenoma of the epididymis)

CaseHPOFreeText: patient was found with retinal hemangioblastomas and epididymal/ovarian cystadenoma at 21Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 1 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: exon 1 deletion

MultipleGeneVariants: N/A

Of 38 PPGL (phechromocytoma and paraganglioma) cases studied, two were associated with individuals carrying the mutation ENST00000256474.2:c.499N>T (ENSP00000256474.2:p.Arg167Trp) of the VHL gene, however one was somatic (VCB.13T) while the other (VCB.14T) was germline. This mutation was identified using Sanger sequencing. The authors identified the reference sequence used as NM_000551.3. Both patients presented with phechromocytoma, and patientID VCB.14T also had 3 other germline mutations present (2 in SDHA, 1 in KIF1B, and the last in MDH2). This patient was previously published in PMID: 25545346.

PatientID: None (Proband)

KindredID: ASP (R167G)

Case: F, 20Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Mutation was absent in mother and two brothers. Proband of this family presented with an apparently sporadic pheochromocytoma and the R167G germline mutation of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Presented with an apparently sporadic unilateral pheochromocytoma. VHL phenotype noted as type 2C.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Clinical evaluation of the three patients indicated the absence of other VHL-related tumors.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167G (c.499C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Variant reported as R167G and cDNA change was mapped to c.499C>G.

MutationType: missense_variant;transversion

CivicName: R167G (c.499C>G)

MultipleGeneVariants: N/A

GroupID: V12

DiseaseAssertion: V12

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity:N/A

GroupAgeRange: N/A

GroupInfo: This family had three members who all had the same VHL germline mutation.

FamilyInfo: Three members of this family had this germline mutation and were affected.

GroupPresentingHPOs:HP:0002666 (pheochromocytoma)

GroupHPOFreeText: This family was classified as VHL type 2B meaning they had a pheochromocytoma and presence of renal and pancreatic manifestations.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82P(c.245G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 193118 https://www.ncbi.nlm.nih.gov/clinvar/variation/193118/

CAID:N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:R82P(c.245G>C)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #58 with 3 affected members who were all genetically confirmed with the mutation. A male proband (patient 155) was diagnosed with retinal angioma at 21Y, renal cell carcinoma at 26Y, and multiple pancreatic cysts/tumors at 26Y. His sister (patient 156) was diagnosed with CNS hemangioblastoma at 21Y and multiple pancreatic cysts/tumors at 27Y. His nephew (son of sister) of unknown age was asymptomatic at the time of analysis. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 239

KindredID: 91

Case: M, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 239) has a sister (patient 240) who presented with multiple pancreatic cysts/tumors at 28.

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

CaseHPOFreeText: The proband presented with a retinal angioma at 14 and a CNS hemangioblastoma at 25.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 23

KindredID: C

Case: Sex Unknown, 9Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: asymptomatic

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient was asymptomatic at the time, likely due to young age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PatientID: III-A

KindredID: 1

Case: M, 45Y0M, EthnicityUnknown

DiseaseAssertion: VHL

FamilyInfo: Multiple first- and second-degree relatives affected with similar phenotypes. Of these, he is genetically tested and found to share VHL mutations with his uncle (proband).

CasePresentingHPOs: N/A

CaseHPOFreeText: Paper asserts that this individual presented with VHL phenotypes but does not specify which.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Information obtained from Figure 1

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: P86S (c.256C>T) and Splice Region (c.340+5G>C)

MultipleGeneVariants: Germline, VHL, L158Q (c.473T>A)

PatientID: 2 (III:2)

KindredID: 1

Case: F, 23Y0M (deceased), Persian

DiseaseAssertion: pheochromocytoma

FamilyInfo: 4 sisters were treated with bilateral adrenal mass resection. Patient 2 died at 23Y and patient 3 died at 21Y due to complications associated with VHL. 2 years later, 3 of their other sisters were found to have the mutation. It is assumed that all 5 of them had the VHL mutation. Their mother and the siblings examined normal, and the father had passed earlier and had a family history of hypertension.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: died at the age of 23 years because of intra operative complications of metastatic bilateral adrenal pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 17

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0006880; HP:0011513; HP:0001737; HP:0000107; HP:0006770 (Cerebellar hemangioblastoma, retinal cavernous angioma, pancreatic cyst, renal cyst, clear cell renal cell carcinoma)

CaseHPOFreeText: Patient had VHL disease type 1: CNS-HB, RA, ccRCC, PC, KCy, and parental mosaicism (see table 1). Previously published 2000 paper (106311387) reports patient as a 48Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10631138

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

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

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 12Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother had pheochromocytoma and positive family history of VHL.

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

CaseHPOFreeText: Retinoblastoma.

CaseNotHPOs: HP:0002668 (Paraganglioma)

CaseNotHPOFreeText: Criteria for exclusion were 1) absence of intra-adrenal tumor, 2) paragangliomas explicitly, 3) extra-adrenal secreting chromaffin tumors, 4) nonsecreting head–neck paragangliomas, 5) no operation, and 6) patients with normal levels of both urinary catecholamines and plasma metanephrines.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 2

Variant: p.G93D (c.278G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496054, https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

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

GenotypingMethod: PCR sequencing analysis.

SamplingMethod: N/A

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma, and pheochromocytoma was available. Case 39 had p.Pro86Leu (c.257C>T) mutation. One member was affected with retinal angioma. Other demographics of the members were not described.

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported variants in legacy variant nomenclature (AF010238.1) so this variant was mapped to c.429_439del (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 26 had a G144fs (c.429_439del) frameshift mutation. 1 member was affected with retinal angioma, CNS hemangioblastoma, and renal cell carcinoma. Other demographics of the members were not described.

PatientID: 50

KindredID: 50

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.E160Qfs*11 (c.477_478insCA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA645525053 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.477_478insCA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: K159fs (c.477_478insCA)

MultipleGeneVariants: N/A

200 patients with intracranial aneurysms were molecularly analyzed for VHL to determine if it is a candidate gene for aneurysm formation using peripheral blood. One patient was analyzed in detail and determined to have the above mutation (183C>G). The patient was only recorded to have an intracranial aneurysm (or dilatation of the cerebral artery).

PatientID: None

KindredID: 48

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, renal cell carcinoma and pancreatic cyst or tumor (unspecified).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96_P97delinsH (c.288_290del)

LegacyVariant: c.501_503del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106244, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.288_290del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: Q96_P97delinsH (c.288_290del)

MultipleGeneVariants: N/A

PatientID: CIV:3

KindredID: C

Case: M, 33Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: A 4-generation family is given with 3 confirmed members with this mutation. 3 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0001737 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic cysts)

CaseHPOFreeText: diagnosed with right renal cell carcinoma, right adrenal pheochromocytoma and multiple pancreatic and renal cysts at the age of 33, but refused genetic screening.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.S80I (c.452G>T)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: No genetic testing was done (patient refused), however family history and presentation leads to this assumption

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 4

Case: M, 32Y0M, 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 32

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: 2

DiseaseAssertion: cerebellar hemangioblastoma

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.162_163insT) was found in 1 VHL family with 2 patients.

GroupPresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

GroupHPOFreeText: both patients had cerebellar hemangioblastomas with a mean age of diagnosis of 19Y

GroupNotHPOs: HP:0005584; HP:0009711; HP:0002666 (renal cell carcinoma; retinal capillary hemangioma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.E55* (c.162_163insT)

CaseProblemVariantFreeText: The mutation was written as follows: AFO10238:375_376insT; NM_000551.2:c.162_163insT; p.54MetX. Author Maher was contacted and confirmed "A single nucleotide insertion (T) was detected at position 375 (375insT)” from 2000 lab report - June 1, 2021 - therefore assume p. was transcribed incorrectly.

LegacyVariant: p.54MetX (c.375_376insT)

ClinVarID: N/A

CAID: CA2499307063 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307063

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: E55* (c.162_163insT)

MultipleGeneVariants: N/A

Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. A germline nonsense mutation (c.525C>A) was found in patient no. 35 from family 7, presenting with pancreatic endocrine tumour. No family history was discussed.

Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. A germline missense mutation (c.482G>A) was found in 3 patients, 2 of which were related. Patient No 5 and No 28 from family 288 both had pancreatic endocrine tumour and pheochromocytoma. Patient No. 21 from family 99 presented with pancreatic endocrine tumour, pheochromocytoma, and renal carcinoma. The patients' phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2). Further, the mutation is occuring at a VHL hotspot (PM1).

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 19 was found with p.Cys162Trp mutation in the VHL gene: 3/3 members had CNS hemangioblastoma and 1/3 had RCC. ACMG PP4

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 summariezed the phenotypes of the families together. Family 3 was found with p.Glu73* mutation in the VHL gene: 5/6 members had CNS hemangioblastoma, 1/6 had RCC, and 1/6 members had a pancreatic lesion. ACMG PP4

PMID: 15918937

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 80

KindredID: 80

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030421 (Epididymal neoplasm)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: complete deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: PCR and direct DNA sequencing. Coding regions and exon intron boundaries of the VHL gen were amplifies and the samples were sequenced by using an automated sequencer (ABI Genetic Analyzwe 3730xi).

SamplingMethod: peripheral whole blood

PatientID: 3

KindredID: 1

Case: Sex Unknown, 39Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584 (hemangioblastoma, pheochromocytoma; retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 16

GroupID/ KindredID: 16

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R108dup (c.322_324dupCGC)

LegacyVariant: Ins. Arg (c.529insGCC)

CaseProblemVariantFreeText: AF010238.1: Ins. Arg (c.529insGCC) translates to: NM_000551.3:c.316_317insGCC which automaps to NM_000551.3:c.322_324dupCGC due to the 3’ rule, so the two are both consistent and possible with this mutation

ClinVarID: N/A

CAID: CA916832608 https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA916832608

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: R108dup (c.322_324dupCGC)

MultipleGeneVariants: N/A

The study included 102 children under age 18 years presenting with various solid tumour types. Patients were predominantly of Asian ethnicities including Chinese (62%), Indian (13%), and Malay (9%). Twelve pathogenic germline mutations in 10 children were identified. Genomic DNA was extracted from peripheral blood usingQIAamp DNA mini kit. Whole exome sequencing was performed using the IlluminaHiseq4000 (Illumina, San Diego, CA, USA). Sequenced reads were aligned to the human reference genome (hs37d5). Candidate variants were validated by Sanger sequencing using BigDyeTerminator v3.1 and resulting chromatograms analysed using Mutation Surveyor. A 7-year old female patient was found to harbour the germline VHL mutation c.191G>C (p.Arg64Pro). The proband had a family history of pheochromocytoma and renal cell carcinoma consistent with VHL syndrome. She presented with a pheochromocytoma and ocular papilloedema. Her mother had pheochromocytoma and her maternal second degree relatives had renal cell carcinoma and systemic lupus erythematosus/rheumatoid arthritis. She was diagnosed with clinical VHL. She showed somatic loss of heterozygosity.

PatientID: 101

KindredID: 101

Case: Sex Unknown, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Single benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.P97L (c.290C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1503290, https://www.ncbi.nlm.nih.gov/clinvar/variation/1503290/

CAID: N/A

gnomAD: N/A

VariantEvidence: Carbonic anhydrase 9 (CA9) mRNA level of 30.92 was detected. Membrane CA9 immunostaining was observed.

MutationType: missense_variant;transition

CivicName: P97L (c.290C>T) and L116P (347T>C)

MultipleGeneVariants: Germline, VHL, L116P (347T>C)

GroupID: 38

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0030393; HP:0001737; HP:0030424 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (2), Spinal hemangioblastoma (2), Endolymphatic sac tumor (1), Pancreatic cysts (2), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, HSPC300, partial deletion

MultipleGeneVariants: Germline, ENST197804, deletion

PatientID: IV-4

KindredID: 1

Case: F, Age Unknown, Mexican

DiseaseAssertion: Asymptomatic

FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: N/A

CaseHPOFreeText: Likely to be asymptomatic due to young age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (a))

Variant: p.R82P (c.245G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P (c.245G>C)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 77Y0M, Taiwanese (East-Asian)

DiseaseAssertion: renal cell carcinoma

FamilyInfo: N/A

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

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

CaseHPOFreeText: She had stage I clear cell renal cell carcinoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21982469

SupplementalData: Yes - Additional file 1: Figure S1

Variant: c.-195G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 342397 https://www.ncbi.nlm.nih.gov/clinvar/variation/342397

CAID: N/A

gnomAD: 0.5796 https://gnomad.broadinstitute.org/variant/3-10183337-G-A

VariantEvidence: RFLP analysis was used to screen for the allele genotype by BsaJ I digestion methods. Heterozygous for both, she also presented with the germline variant c.*294G>A in VHL. LOH (A) of both mutations was found in the tumor tissue as well

MutationType: 5_prime_UTR_variant

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

MultipleGeneVariants: Germline, VHL, c.*294G>A

PatientID: None

KindredID: 6

Case: age, sex, ethnicity unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: Sex Unknown, 65Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0000107; HP:0001737; HP:0002666 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst, Pancreatic cysts, Pheochromocytoma)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

56 male patients age 12 to 76 years, from 40 families with VHL were examined as part of a larger screening program for VHL. VHL mutations were identified in 16 families. Individual patient phenotype-genotype data was not available, but the mutations found and whether the corresponding patient had epididymal cystadenoma (EC) was reported. A p.W88R (c.262T>A) VHL mutation was found in a VHL patient with EC. This mutation was referred to in the paper as c.475T>A due to a difference in transcript sequence.

PatientID: 2

KindredID: 2

Case: M, 22Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history present.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Bilateral involvements of retinal HB (See table 1)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 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

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

GenotypingMethod: miRNA expression profiling was performed using the Agilent Human miRNA Microarray Kit version 2.0 (G4470B, Agilent Technologies). First-strand cDNA synthesis by RT of total RNA was performed using the miRCURY LNA Universal RT miR PCR system (Exiqon, Vedbaek, Denmark) according to the manufacturer's recommendations. Quantitative real-time PCR (qRT-PCR) were performed on an ABI PRISM 7900HT analyzer (Applied Biosystems).

SamplingMethod: frozen tumours and formalin-fixed paraffin-embedded specimens

Of 31 Brazilian patients, one was found to harbour the c.463+1G>A intronic 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 45, presented with renal cyst, pancreatic cyst and 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.

GroupID: 10

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 1 member is stated to have retinal HBs. Other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: the other 1 patient is said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

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: 7 (tumour 9,10,11)

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient presented with three benign pheochromocytomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID:4

KindredID: A

Case: M, 25Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E94K (c.280G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 135955 https://www.ncbi.nlm.nih.gov/clinvar/variation/135955/

CAID: N/A

gnomAD: 0.000004460 https://gnomad.broadinstitute.org/variant/3-10183811-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_transition

CivicName: E94K(c.280G>A)

MultipleGeneVariants: N/A

PatientID: 223

KindredID: 223

Case: Sex Unknown, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive family history for VHL.

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q(c.500G>A)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 1 (group ID 5)

Case: M, 51Y0M, Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 9’s father and brother had this familial mutation. His one daughter had not been yet tested at the time of the study. See Fig 4 for family pedigree; Table 3 for details.

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

CaseHPOFreeText: He had CNS hemangioblastomas at 35Y and RCC at 42Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

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