PatientID: II-3

KindredID: 1

Case: 51Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: Family suggesting incomplete penetrance of a VHL gene germline mutation. Mutation (p.R64P) was found in a family with 6 patients total with three generations. The earliest patient described (I-1) presented with renal cell carcinoma (age at diagnosis 48 years), 1 of their 6 children (II-1) at age 59 had no typical VHL manifestations after annual clinical monitoring and suggest non-penetrance in the patient; the second of 6 children (II-3), then aged 51, had bilateral pheochromocytoma diagnosed age 14. Their only child (III-5) had a paraganglioma with an age of diagnosis of 29 years, and a renal cyst. Patient II-1 had 4 children - one (III-1; aged 40) who presented as a carrier with no typical VHL manifestations after annual clinical monitoring; and another 32 years old presenting with pheochromocytoma. (See Figure 2 for pedigree)

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma diagnosed at age 14

CaseNotHPOs: N/A

CaseNotHPOFreeText: Unclear as to whether testing for other manifestations was conducted

CasePreviousTesting: N/A

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

SupplementalData: N/A

Variant: p.R64P (c.191G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: CA020089 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.191G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 31

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Reported as familial VHL - no further information provided

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001737; HP:0002666; HP:0000107; HP:0010797; HP:0009711 (pancreatic cysts, pheochromocytoma, renal cyst, hemangioblastoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: IVS1+1G>A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 21

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL; One registrant belonging to family 21 has the germline VHL mutation of c.490C>T.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0030424 (hemangioblastoma, renal cell carcinoma, epididymal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0001737; HP:0005584; HP:0002666 (retinal capillary hemangioma, pancreatic cysts, renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: N/A

Variant: p.Q164* (c.490C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223228 https://www.ncbi.nlm.nih.gov/clinvar/variation/223228/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q164* (c.490C>T)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. 3 families have mutation R167Q(c.500G>A) in the VHL gene. Family 15 has 5 affected members: 4 members had retinal capillary hemangioma, 3 members had CNS hemangioblastoma, 2 members had renal cell carcinoma, 3 members had renal cysts, 1 member had pheochromocytoma, 1 member had pancreatic cysts, 2 members had endolymphatic sac tumor and 1 member had adnexal pipillary tumor of probable mesopnephric origin. Family 16 has 4 affected members: 2 members had retinal capillary hemangioma, 2 members had CNS hemangioblastoma, 1 member had renal cell carcinoma, 4 members had pheochromocytoma and 1 member had endolymphatic sac tumor. Family 17 has 2 affected members: 1 member had retinal capillary hemangioma, 1 member had CNS hemangioblastoma and 1 member had renal cell carcinoma. ACMG: 'PP4' because the patient's phenotype and family history are highly specific for a disease with single genetic etiology.

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 13 has two affected members. Genetic analysis reveals mutation L158P(c.473T>C) in the VHL gene. Both members of the family presented with pheochromocytoma.

33 patients diagnosed with VHL disease, according to (Maher et al. 1990), were tested for germline VHL mutations. Genetic testing was performed on high-molecular-weight DNA from peripheral blood using Southern analysis and PCR. Four patients from 3 families (95, P1, P30) were found to harbour the 499C>T (Argl67Trp) VHL gene mutation, documented in the paper as 712C>T due to an older transcript used. Patient P30/1 presented with both pheochromocytoma and a cerebellar hemangioblastoma. Patient P1/1 presented with pheochromocytoma and a cerebellar hemangioblastoma, and their family member, patient P1/2 presented with two cerebellar hemangioblastomas. Patient 95/1 presented with pheochromocytoma. ACMG evidence codes: 'PP1' since we have cosegregation with the disease in multiple affected family members (family P1), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Eleven patients were found with the missense variant, c.500G>A, in the VHL gene. The ages of the patient was represented as a range, 21-65Y. The phenotypes were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, pheochromocytoma, renal cysts, and pancreatic cysts. Family history was not described. The group was classified as a 2a/b meaning that it included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.

GroupID: 6A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174 https://www.ncbi.nlm.nih.gov/clinvar/variation/223174/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

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. 22 patients were found to have the above mutation (c.499C>T). 7 were VHL patients with ICTs (pancreatic neuroendocrine tumors) taken from the VHL-registry. The other 15 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. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation (c.349T>C) was detected by direct sequencing and MLPA and was found in a VHL patient (case no. 25823). Phenotype not described. Germline, Inconclusive whether de novo.

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation was detected by direct sequencing and MLPA. This missense mutation (c.452T>G) was found as a sporadic germline in a VHL patient with CNS hemangioblastoma (case no. 29982). The case was suspected to be de novo but this could not be confirmed. ACMG PM6

PatientID: N/A

KindredID: 7250, 17991

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states familial VHL; no obvious relation (family surnames, location) but could be distantly related

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001407; HP:0000107; HP:0005584 (hemangioblastoma; pancreatic cysts; hepatic cysts; renal cyst; renal cell carcinoma)

CaseHPOFreeText: Patient had CNS HB, pancreatic/ hepatic/ renal cysts and RCC

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

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: N/A

PatientID: N/A

KindredID: 177

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states familial VHL; no obvious relation (family surnames, location) but could be distantly related

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: had multiple HB of the CNS

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: p.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 11

Case: M, 48Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: His son also had the mutation and had a CNS hemangioblastoma. The mother and sisters of patient 11 were also suspected to have VHL mutations, but their DNA was not evaluated.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

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

CaseHPOFreeText: Patient 11 presented with nausea, vomiting, and left-side weakness, developed within 2 days. MR brain images revealed a hemangioblastoma-like cystic mass in the cerebellum (age 36) . He therefore underwent cerebellar tumor resection. When he was under observation, retinal hemangioma and renal cell carcinoma were detected at the ages of 41 and 48 years, respectively. He also had renal cysts at age 48.

CaseNotHPOs: HP:0001732, HP:0002666 (abnormality of the pancreas, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: Sister

KindredID: 5

Case: F, Age Unknown, Korean

DiseaseAssertion: Assumed VHL

FamilyInfo: Brother (Proband) presented with CNS hemangioblastoma at 112Y, bilateral RCC at 19Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 13Y and was found to harbor the p.Phe76del (c.227_229del) VHL variant. Other brother presented with CNS hemangioblastoma at 19Y, bilateral RCC at 18Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 23Y and bilateral cysts at 19Y but was not genetically confirmed. Father presented with CNS hemangioblastoma at 27Y, bilateral RCC at 44Y, pheochromocytoma at 44Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 44Y and bilateral renal cysts at 44Y but was not genetically confirmed.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: N/A

CaseHPOFreeText: Presented with developmental venous anomaly or meningioma (unspecified).

CaseNotHPOs: HP:0002666; HP:0000107; HP:0009711; HP:0010797; HP:0005584; HP:0001732 (Pheochromocytoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transversion

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The P154= (c.462A>C) mutation was found in two VHL type 2A (with pheochromocytoma) family members (patient/proband no. V78). Two unaffected family members did not harbor this synonymous mutation.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France). No variants were found in 96 control cases. This missense mutation, c.245G>C, was found in 3 VHL type 2B family members (kindred no. V12), but not in 7 unaffected family members. Type 2B VHL families are described as having pheochromocytoma and presence of renal and pancreatic manifestations.

43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 1 (patient VHL-3) of the 43 patients was found to have the Val194Alafs*61 (c.579_580del) germline mutation of the VHL gene. Genotyping was performed on peripheral blood executed via direct sequencing on an automatic sequencer and real time quantitative PCR. Clinical manifestations associated with this mutation include: CNS hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma, and renal cysts. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

PatientID: VHL-7

KindredID: 7

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

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:0005584; HP:0009711; HP:0000107 (Renal cell carcinoma, Retinal capillary hemangioma, Renal cyst)

CaseHPOFreeText: Bilateral renal cell carcinoma. Clinical classification: A2.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0001732 (Hemangioblastoma, Pheochromocytoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Sfs*5 (c.499_504delinsT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621943, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499_504delinsT

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName: R167Sfs*5 (c.499_504delinsT)

MultipleGeneVariants: N/A

This report studied the prevalence of germline variants in Japanese PPGL patients. Of the 370 PPGL original Japanese probands, this cohort consisted of 15 patients with pheochromocytoma and/or paragangliomas with germline VHL varaints. Blood samples were used to examine 7 genes: MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET, using Sanger sequencing. Of these 15 VHL patients: 10 had bilateral PCC, 4 had PCC with abdominal/thoracic PGL, and one had metastatic PPGL. The variant V84M (c.250G>A) was one of the 15 found in a patient with PPGL. Their family history or further manifestations were not detailed.

PatientID: 244

KindredID: 94

Case: M, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 244) has a daughter with the variant (patient 245) who was asymptomatic at the time of assessment.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 28, renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 40, and retinal angioma at age 41.

CaseNotHPOs: N/A

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

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 found in family #34 with 5 affected members and the mutation genetically confirmed in 2 patients. A male proband was diagnosed with CNS hemangioblastoma at 40Y, retinal angioma at 40Y, renal cell carcinoma at 40Y, multiple pancreatic lesions at 40Y, and pheochromocytoma at 40Y. His first sister was diagnosed with CNS hemangioblastoma at 51Y and retinal angioma at 51Y. His mother, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 50Y and multiple pancreatic lesions at 63Y. His second sister, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 40Y, renal cell carcinoma at 43Y, and multiple pancreatic lesions at 43Y. His brother, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 27Y and retinal angioma at 27Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336). It is likely that all three papers published the same family.

PatientID: 281

KindredID: 110

Case: M, 29Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22. Their father presented with a CNS hemangioblastoma at age 25, and retinal angioma at age 29.

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

CaseHPOFreeText: The proband's father presented with a CNS hemangioblastoma at age 25, and retinal angioma at age 29.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 234

KindredID: 87

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother, patient 235, passed away before diagnosis/ germline testing, but presented with multiple pancreatic cysts/tumors at age 38.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and multiple pancreatic cysts/tumors at age 27.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: c.565_570del (p.E189_D190del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320338, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320338

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: E189_D190del (c.565_570delGAAGAC)

MultipleGeneVariants: N/A

PatientID: 31

KindredID: 463

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184H (c.551T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756352 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.551T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L184H (c.551T>A)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: M, 14Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient was found to have multiple benign tumour 4 cm in size in his adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHC/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65T(c.193T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351748794 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.193T%3EA

gnomAD: N/A

VariantEvidence: The patient had LOH of SDHC as indicated in Table 1.

MutationType: missense_variant;transversion

CivicName: S65T(c.193T>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 (D121fs (c.361delG)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 147CA. It was reported in the paper as c.574delG due to a difference in transcript reference. Table 5 lists all ID and mutations associated with individuals without detailed clinical information. Other phenotypes are possible, however not detailed here.

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 (P59fs (c.175delC)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 56CA. It was reported in the paper as c.388delC due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL family 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 (L118P (c.353T>C)) was taken from multiple databases including: the Department of Uroglogy, Yokohama database, the Cambridge, Department of Pathology database, and the Neuro Olcologie database in Paris, with an unknown number of members belonging to Family IDs 46YO, 19CA, 27F. It was reported in the paper as c.566T>C 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 (S65* (c.189_192del)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 19BMS. It was reported in the paper as c.402_405del4 due to a difference in transcript reference. Table 5 lists all ID and mutations associated with individuals without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupID/ KindredID: 105CA, 109CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to two family IDs: Family 105CA and 109CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 9829912

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 13BMS

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 13BMS. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Of 14 patients with retinal vascular proliferation and known family history of VHL disease, 12 patients were enrolled in an approved study protocol at the National Cancer Institute. 11 of these patients underwent genetic testing and were found to have mutations in the VHL gene. Patient 7, age 34, was diagnosed with retinal vascular proliferation, pancreatic and renal abnormalities. She was not found to have any morphological central nervous system abnormalities. Genetic testing revealed that she harboured the c.526delA mutation in the VHL gene (stated as c.739delA in the paper which used the Latif sequence as reference). ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 1

KindredID: D

Case: F, Age Unknown, Japanese

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s family consisted of seven members, but only the patient’s brother carried the same missense variant NM_000551.3:c.484T>C the patient carried and developed symptoms.

CasePresentingHPOs: HP:0006880; HP:0011513 (Cerebellar hemangioblastoma, retinal angioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162R(c.484T>C)

LegacyVariant: p.C233R(c.697T>C)

ClinVarID: N/A

CAID: CA351756117, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351756117

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: C162R(c.484T>C)

MultipleGeneVariants: N/A

GroupID: 29a

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 3/4 patients with a R107G (c.319C>G) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 4

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other members of his family had this VHL mutation (Patients 6, 7, 8, 10).

CasePresentingHPOs: HP:0002668, HP:0002666, HP:0000107, HP:0001737, HP:0010797(Paraganglioma, pheochromocytoma, renal cyst, pancreatic cysts, hemangioblastoma)

CaseHPOFreeText:The patient was diagnosed with paraganglioma and pheochromocytoma at age 49.

CaseNotHPOs: HP:0009711, HP:0005584, HP:0030405 (retinal capillary hemangioma, renal cell carcinoma, pancreatic endocrine tumor)

CaseNotHPOFreeText: Although patient 4/9 is reported in Table 4 to have a pancreatic endocrine tumour this is believed to be a typo and actually be information on patient 4/10.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: Mother

KindredID: 1

Case: F, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Son presented with the same germline VHL variant as well as headache, diplopia, pheochromocytoma, hypertension and retinal capillary hemangioma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Had been operated for bilateral pheochromocytoma at the age of 23 and had not been under medical follow-up since then.

CaseNotHPOs: HP:0009713; HP:0006880; HP:0009711 (Spinal hemangioblastoma, Cerebellar hemangioblastoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: The patient's mother was evaluated by ophthalmologic examination and no abnormalities were found. She underwent cerebral and spinal MRI and abdominal CT to investigate any possible VHL tumors, and no tumor was detected.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.695G>A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant was reported as “c.695G>A” which was mapped to p.Arg161Gln (c.482G>A) in accordance with reference sequence NM_000551.3.

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: VI-2

KindredID: 1

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient’s great-grandmother and two great-uncles had died with cerebellar hemangioblastoma, although genetic testing was not performed. The patient’s grandfather presented with cerebellar hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, and serous cystadenoma at 68Y, adrenal pheochromocytoma at 73Y, and clear cell renal cell carcinoma metastasis in the thyroid at 74Y; he was found to carry the same mutation the patient carried. The patient’s father, a 46Y male, also presented with a small renal tumour, renal cysts, and pancreatic cysts. Genealogical inquiry also revealed that the patient was distantly related to a known VHL family; one member, a 47Y male, was previously operated on for CNS hemangioblastoma, RCC and symptomatic pheochromocytoma and was found to carry the same mutation as the proband. Another female member had previously presented with retinal hemangioblastoma before becoming deceased at 37Y. The paper also asserted that the patient’s grandmother and two distant relatives carried the mutation, although genotyping was not performed and phenotypic information was not provided.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P(c.245G>C)

MultipleGeneVariants: N/A

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.R161* (c.481C>T) mutation, 15 members total from 10 families were described, and phenotypic information was given for this group. With ages of onset ranging from 14-47Y, hemangioblastomas were observed in 12/15 members, retinal capillary hemangioma in 1, renal cell carcinoma in 10, pancreatic cysts in 9, pheochromocytoma in 1 member and and a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) in 2 members. PMID 28388566 and 29330336 previously report this cohort.

PatientID: 13

KindredID: 2

Case: M, 33Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: bilateral pheochromocytoma sized R: 6.8cm , L: 3.6cm; Grade 2 clear cell renal cell carcinoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/TMEM127

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.R64P (c.191G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: See table 4 for SDHB information; See table 6 for THEM127 information

MutationType: missense_variant;transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: Somatic, TMEM127, c.621G>A (p.Ala207Ala)

Tissues embedded in paraffin blocks were collected from 203 cHAB patients operated in different Medical Centres in Poland. Eight of these harboured germline mutations in unrelated patients from distinct undiagnosed VHL families. Various variants were unverified as somatic or germline as they were detected in tumour but blood samples were not tested. Other phenotypes and demographic information is not known. Patient 50 was found with a germline frameshift mutation in the VHL gene. ACMG PP4

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. Patient IDs 30, 31, 32, 33, 34, 35, 36, 37, and 48 were found with this germline mutation (S65A (c.193T>G)). Whether patients were related, age, and sex data was not reported in this paper, although they were previously reported under PMID: 29437867. All patients except for 33 had neuroendocrine neoplasms, and 30, 31, 32, 33 34, 36 also had hemangioblastomas. 1 patient (32) also had ccRCC.

PatientID: 52

KindredID: 52

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (asymptomatic)

FamilyInfo: N/A

CasePresentingHPOs: None

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

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

Variant: Deletion of Exon 2

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 deletion

MultipleGeneVariants: N/A

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. 4 patients were found with this germline mutation (c.499C>T). Whether patients were related, age, and sex data was not reported in this paper. Patient 77 was asymptomatic, and patient 79 had a hemangioblastoma, retinal capillary hemangioma, and clear cell renal cell carcinoma. They were both previously reported under PMID: 29437867. Patient ID 41 and 68 were found with this germline mutation (c.499C>T). Patient 41 had CNS hemangioblastoma; renal cell carcinoma; pancreatic endocrine tumor; and pheochromocytoma/paraganglioma. Patient 68 had pheochromocytoma/paraganglioma.

PatientID: 73

KindredID: 73

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030405; HP:0030421; HP:0006770 (Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm; clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.L128Ffs*31 (c.381del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625241 https://www.ncbi.nlm.nih.gov/clinvar/variation/625241/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: L128Ffs*31 (c.381del)

MultipleGeneVariants: N/A

Eleven RCCs and 16 renal cysts from eight patients with VHL were analyzed. All patients had known germline VHL mutations. One male patient had a germline missense mutation (c.486T>G; p.Y156*) in the VHL gene and presented with unilateral RCC and cysts, CNS hemangioblastoma, and pancreatic cysts. Family history was not described for the patient.

GroupID: 25

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

PatientID: II

KindredID: 7

Case: Sex Unknown, 36Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: One other family member presented with this variant as well as 3 retinal hemangioblastomas (8Y and 16Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 13Y. Age at the end of study: 36Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. One family with 3 patients (Family ID15) was found with a germline missense mutation in the VHL gene (V166F; c.496G>T). Patient 1 was diagnosed at 6Y and had no manifestations by the end of the study at age 23Y. Patient 2 was diagnosed at 8Y and had 2 pheochromocytomas at 8Y, 2 CNS hemangioblastomas at 12Y and 13Y, and 2 retinal hemangioblastomas at 8Y and 12Y. Patient 2 was 53Y by the end of the study. Patient 3 was diagnosed at age 15Y and had 2 pheochromocytomas at 15Y. Patient 3 was 60Y by the end of the study.

PatientID: I

KindredID: 3

Case: Sex Unknown, 18Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: 3 other family members presented with his VHL mutation. Patients 3-II and 3-III both presented with pheochromocytoma at 15Y. Patient 3-IV presented with 2 pehochromocytoma (12Y) and retinal hemangioblastoma (10Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 7Y. Age at the end of study: 18Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

PatientID: None

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Not specified

FamilyInfo: Many of the patient’s family members developed lesions in sites suggesting VHL including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and some of the family members have lost their sight because of retinal detachment (probably in the case of retinal haemangiomas). However, the diagnosis of VHL has not been established in the family. One of the patient’s siblings and the patient’s father were also found to have the NM_000551.3:c.194C>T(S65L) mutation after analysis of blood samples, and the patient’s father had an endolymphatic sac tumour at 19Y and a recurrence at 21Y. At 24Y, his father had a hemangioblastoma and had a recurrence at 26Y. His father also had a history of retinal capillary angioma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.S65L (c.407C>T)

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

gnomAD: 0.000, https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

PatientID: VI-2

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

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

CaseHPOFreeText: Retinal angioma and renal cyst. Age of onset not provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

PatientID: 026

KindredID: 1

Case: F, 25Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: No family information reported.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had bilateral pheochromocytoma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, NF1, RET, TMEM127, VHL, SDHA/SDHB/SDHC/SDHD/SDHAF2

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 22199, https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transversion

CivicName: R167G (c.499C>G)

MultipleGeneVariants: N/A

PatientID: 35 (Grandmother)

KindredID: 1

Case: F, 83Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. IDs 1 (proband), 28, 2, 6, 17 and 19 all presented with pheochromocytoma. ID 5 presented with CNS hemangioblastoma, retinal angioma and renal cyst OR tumor (not specified). ID 21 presented with retinal angioma and pheochromocytoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: Died at age 83.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0000077; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Renal cell carcinoma, Abnormality of the pancreas, Abnormality of the kidney, Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.S65A (c.193T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223160, https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 4 (Cousin)

KindredID: 7

Case: M, 5Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family were found to harbor the c.319C>G germline variant of the VHL gene. ID 11 presented with renal and pancreatic abnormalities, pheochromocytoma and other undefined phenotypes. ID 1 presented with pheochromocytoma. ID 2 presented with pancreatic abnormalities. ID 10 presented with CNS hemangioblastoma, pancreatic abnormalities and pheochromocytoma. ID 24 presented with renal abnormalities, and pheochromocytoma, and died at age 62.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with pheochromocytoma (5Y).

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0010797; HP:0000077 (Retinal capillary hemangioma, Renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: This patient presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: Exon 3 Deletion (c.464-11 T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2573331912, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573331912

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10191460T>A; c.464-11 T>A (cDNA change)

MutationType: deletion; splice_site_variant

CivicName: Exon 3 deletion (c.464-11 T>A)

MultipleGeneVariants: N/A

VHL germline mutation carriers who had an ophthalmologic examination at the Erasmus Medical Centre or the Rotterdam Eye Hospital between 1984 and 2017, and were diagnosed with retinal hemangioblastoma (RH) were included in this study. A diagnosis of RH was based on the clinical appearance of a vasoproliferative retinal tumour. Peripheral blood samples from every member that had clinically suspected VHL disease of each family were collected for VHL mutation analysis. A total of 21 patients from 10 families were included on the basis of both a VHL germline mutation and ocular manifestations. Copy number analyses were carried out by multiplex ligation dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH). Mutations were described as one of the following two groups: truncating (complete deletion, partial deletion, nonsense mutation, splice site mutation, duplication and insertion) or missense. Ocular manifestations were not reported on an individual level, but rather were broken down based on the two groups. From Pedigree (family) 13, one individual was suspected of VHL disease and mutational analysis revealed a L89P(c.266T>C) missense variant. This individual did not develop RH.

GroupID: 15

DiseaseAssertion: VHL

Group size: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, 2 individuals were suspected of VHL disease, but none developed RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: None of the VHL patients presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: Complete VHL Deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

Case report of a female VHL patient presenting with spinal hemangioblastoma at the age of 32Y. This was originally misdiagnosed as nerve sheath tumour in the cauda equina. Further workup showed the presence of pancreatic cysts and a history of spinal hemangioblastoma in the mother. Genetic testing confirmed the presence of the p.E94*(c.280G>T) mutation in the proband. There was no mention of genetic testing performed on her mother in this paper. Not explicitly said to be germline, however family history gives presumption, and: “the final diagnosis of VHL is based on the VHL gene mutation analysis and the demonstration of clinical manifestation. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology.

PatientID: V-7

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

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

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: IV-13

KindredID: 2

Case: M, 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

PatientID: IV-13

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

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

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

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

GenotypingMethod: The genetic analysis was performed through PCR analysis of the VHL gene

SamplingMethod: N/A - Not stated

PMID: 9523203

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: None

KindredID: 23

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: Total of 3 family members belonging to Family 23 (see Table 2; or follow KindredID 23). The 2 other members were found to be asymptomatic.

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

CaseHPOFreeText: At initial screening (and same by final 5 year follow up) patient was found with 2 HB, bilateral retinal capillary hemangioma, a renal cyst, and RCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E134* (c.400G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 1069709 https://www.ncbi.nlm.nih.gov/clinvar/variation/1069709/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: E134* (c.400G>T)

MultipleGeneVariants: N/A

PatientID: 1 (I:1)

KindredID: 1

Case: M, 46Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: large family history of VHL was tested - 3 members found. The patient's sister and her daughter had the same mutation - His sister (patient 2) had cerebellum hemangioblastoma at 38Y and a neoplasm of both kidneys at 40Y

CasePresentingHPOs: HP:0006770; HP:0010797; HP:0000107; HP:0001737 (clear cell carcinoma; Hemangioblastoma; renal cysts; pancreatic cysts)

CaseHPOFreeText: had pain in both upper limbs and was diagnosed with spinal hemangioblastoma. At 43Y he was diagnosed with ccRCC in his right kidney, as well as the above manifestations

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 22398592

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 3

Case: 31Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma reported with an age at diagnosis of 31 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R167W (c.499C>G)

MultipleGeneVariants: N/A

PatientID: 18

KindredID: 11

Case: 13Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Recorded as an apparently sporadic tumor; no family info present

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma reported with an age at diagnosis of 13 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: 19958924

SupplementalData: N/A

Variant: p.Y156C (c.467A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

Frequency of VHL, RET, SDHD, SDHC, and SDHB germline mutations in 21 patients clinically classified as having apparently sporadic pheochromocytomas or paragangliomas was assessed. Germline variations were found in 7 of 21 patients. This missense mutation (Y156C (c.467A>G)) was found in a 13 year old patient with sporadic, bilateral pheochromocytomas (patient no. 18).

PatientID: 230

KindredID: 230

Case: Sex Unknown, 40Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0001732; HP:0009711 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17006605

SupplementalData: Table S1, S2 and S3

Variant: c.-61_-51dup

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 517152, https://www.ncbi.nlm.nih.gov/clinvar/variation/517152/

CAID: N/A

gnomAD: 0.00009581, https://gnomad.broadinstitute.org/variant/3-10183466-C-CTCCGCCCCGCG?dataset=gnomad_r2_1

VariantEvidence: Variant was reported as c.-65_-55dup11 which was mapped to c.-61_-51dup.

MutationType: splice_site_variant; duplication; plus_2_frameshift_variant; 5_prime_UTR_variant

CivicName: c.-61_-51dup11

MultipleGeneVariants: N/A

PMID: 17004871

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID: 320

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to have the c.525C>A germline variant of the VHL gene. Member 7851 presented with severe renal disease (RCC) and member 7547 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1298905, https://www.ncbi.nlm.nih.gov/clinvar/variation/1298905/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

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

MultipleGeneVariants: N/A

GroupID: 94

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.407T>C germline variant of the VHL gene. Member 1322 presented with moderate renal disease (RCC). Member 5602 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 2 and 2 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. One or both of these previously reported patients could correspond to family 53 in the current paper.

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

Variant: p.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064, https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

GroupID: 48

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.345C>G germline variant of the VHL gene. Members 971 had no renal involvement. Member 1642 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 individual with this mutation is reported in both. It is unclear if one or both of these previously reported groups are the same as the current family.

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

Variant: p.H115Q (c.345C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496058, https://www.ncbi.nlm.nih.gov/clinvar/variation/496058/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H115Q (c.345C>G)

MultipleGeneVariants: N/A

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.R108Lfs*52 (c.322_323insTG) germline variant of the VHL gene was detected in an individual (ID 7601, Family 321). The patient presented with renal cell carcinoma. No family information is provided. The paper states that this patient is previously reported in PMID ​​12202531.

PatientID: 3

KindredID: C

Case: F, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Hemangioblastoma

FamilyInfo: Positive: The patient’s sister, one of two brothers, and mother each had the same germline mutation, although without any manifestations. As such, her family history was negative for kidney cancer, hemangioblastoma, or other features of VHL. See Fig. 3.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: In 2013, at 32Y, patient presented with a hemangioblastoma in her cerebellar region.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No other VHL- related tumors are present in this patient.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.L63fs*4 (c.188_188T>TG)

LegacyVariant: N/A

CaseProblemVariantFreeText: NM_000551.3:c.188_188T>TG automapped to c.189dupG, (p.R64Afs*68)

ClinVarID: 496050 https://www.ncbi.nlm.nih.gov/clinvar/variation/496050/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: R64fs (c.189dupG)

MultipleGeneVariants: Germline, VHL,c.241C>T (p.Pro81Ser)

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

GenotypingMethod: N/A - germline methods not specified

SamplingMethod: blood

51 patients with with local-regional recurrence of sporadic or syndromic extra-adrenal paraganglioma were thoroughly analyzed for clinical characteristics, biochemical and imaging results, operative notes, molecular analysis, and pathology reports. 1 patient was found to have the above VHL mutation (c.467A>G). Clinical manifestations included a left para-aortic paraganglioma, and cervical paraganglioma. ACMG evidence codes: 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease.

PMID: 18416845

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). The mutation Y156C (c.467A>G) was detected in the patient, referred to in the paper by c.680A>G due to a difference in transcript sequence. This missense mutation was found in the VHL gene and two patients with pheochromocytoma. Any relation is unstated.

PatientID: N/A

KindredID: 9

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A - said to be spontaneous

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Nonsyndromic pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R107G (c.532C>G)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Said to have been a spontaneous mutation

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: III-48

KindredID: 1

Case: F, Age unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

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

CasePresentingHPOs: None

CaseHPOFreeText: VHL found by genetic testing not clinical findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.688delA

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: N/A

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

GenotypingMethod: PCR of all exons of VHL, SDHB, and SDHD genes was performed; Denaturing high performance liquid chromatography (dHPLC) analysis too.

SamplingMethod: blood leukocytes (from stored blood samples)

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. The p.P158L (c.473T>C) mutation was detected in the patient, referred to in the paper by c.686T>C due to a difference in transcript sequence. This missense mutation was found in a VHL type 2B family of 51 individuals (family ID 4485). 25 individuals were identified with retinal hemangioblastomas, 32 with cerebellar hemangioblastomas, 29 with renal cell carcinoma, and only one with pheochromocytoma. Mutation also found in a VHL type 1 family of 25 individuals (family ID 4408). Two of 25 individuals carried renal cell carcinoma, 14 carried angiomas, and 16 carried cerebellar hemangioblastomas. ACMG codes as follows: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (PS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).

This paper describes the clinical and genetic findings of 36 Spanish pediatric patients with pheochromocytoma or paraganglioma. Genetic testing involved sequencing and MLPA of VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. The molecular analysis identified 8 patients with variants in the VHL gene. The missense mutation, c.482G>A, was found in two patients; patient 23 presented with pheochromocytoma (onset age 18) while the patient 18 had pheochromocytoma and thoracic-abdominal paraganglioma (onset age 9). The latter patient is said to have been previously reported, although it is not specified where.

PatientID: 23

KindredID: 2

Case: F, 18Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: No family history, assumed de-novo, but unclear if parents were tested to confirm de-novo assertion.

CohortInfo: 36 pediatric patients with pheochromocytomas and/or parangangliomas.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient was found to have a benign norepinephrine secreting pheochromocytoma at age 18.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, the authors show that the mutations in E1' induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. 6/10 genetically tested family members (family F8) across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma. These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity.

KindredID: 151

GroupID: 28

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 151 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: No additional phenotypic information is listed for this kindred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L153Tfs*21 (c.456dup)

LegacyVariant: p.223FS (c.668insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2499307154

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: L153Tfs (c.456dup)

MultipleGeneVariants: N/A

KindredID: 146

GroupID: 2

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 146 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. No family history is provided.

GroupPresentingHPOs: N/A

GroupHPOFreeText: No phenotypic information is listed for this kindred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A56Sfs*76 (c.165_166insA)

LegacyVariant: p.126FS (c.378insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524648, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.165_166insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: A56fs (c.164_165insA)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 1

Case: F, 66Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Patient’s nephew (index case) is a 52Y0M man diagnosed with five cancers (clear cell renal cancer, glioma, low-grade urothelial tumour, Cutaneous basal cell cancer, Multifocal bilateral papillary thyroid cancer) from the age of 40Y0M. The nephew had a heterozygous CHEK2 variant but no VHL mutation. Patient’s sister (mother of index case) died of non-Hodgkin’s lymphoma at 47Y0M in 1993. The patient’s niece (sister of index case) was diagnosed with breast cancer at the 26Y0M and died at 27Y0M in 1999. Neither the patient’s sister nor niece had genetic testing.

CasePresentingHPOs: HP:0002666; HP:0003002 (pheochromocytoma, breast carcinoma)

CaseHPOFreeText: Patient was diagnosed with pheochromocytoma at the age 56Y0M and breast cancer at age 66Y0M.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: next-generation sequencing for MAX, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and multiplex ligation-dependent probe amplification (MLPA) for VHL, SDHA, MAX, SDHB, SDHC and SDHC.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330, https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988, https://gnomad.broadinstitute.org/variant/3-10183605-C-T