PatientID: CIV:7

KindredID: C

Case: F, 29Y0M, Chinese

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0002666; HP:0010797 (pheochromocytoma, hemangioblastoma)

CaseHPOFreeText: initially diagnosed by genetic analysis and further verified radiologically and surgically - found with CNS hemangioblastomas and pheochromocytoma at 29Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 43

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0002894; HP:0002666 (hemangioblastoma, renal cell carcinoma, neoplasm of the pancreas, pheochromocytoma)

CaseHPOFreeText: 1 HB at initial screening, as well as an additional 3 HB, 2 RCC, 1 pheochromocytoma, and pancreatic cancer at final screening (5 year follow up).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: None (III)

KindredID: 1

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: hemangioblastoma

FamilyInfo: Total of 4 family members belonging to Family 1 (see Table 2; or follow KindredID 1)

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: 4 HB at first screening, and same by final screening (5 year follow up).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223166 https://www.ncbi.nlm.nih.gov/clinvar/variation/223166/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: p.F76del

MultipleGeneVariants: N/A

PatientID: None

KindredID: 20

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0001737; HP:0005584; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cyst, pancreatic cysts, renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: At initial screening, patient was found with 2 HB, unilateral retinal capillary hemangioma, 1 renal cyst, 1 pancreatic cyst, and 1 pheochromocytoma. By final screening, the 5 year follow up, there was an additional RCC and pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162F (c.485G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43604 https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162F(c.485G>T)

MultipleGeneVariants: N/A

PatientID: None (III)

KindredID: 6

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: Total of 6 family members belonging to Family 6 (see Table 2; or follow KindredID 6)

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0001737; HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cyst, pancreatic cysts, renal cell carcinoma)

CaseHPOFreeText: 1 HB, bilateral RA, pancreatic and kidney Cysts during first screening; with the addition of +2 RCC by final status

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: None (VI)

KindredID: 6

Case: Sex and Ethnicity unknown; Age <18Y0M

DiseaseAssertion: Asymptomatic

FamilyInfo: Total of 6 family members belonging to Family 6 (see Table 2; or follow KindredID 6)

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 4

Case: F, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had a right temporal hemangioblastoma at age 25. After surgery the patient was disease free. The patient was followed up 16 years later.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2-3 Deletion

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

Study of a German family of 16 family members with cosegregation of the pheochromocytoma-only phenotype with two concurrent germline mutations in the VHL protein alpha and beta domains. These mutations were c.562 C>T (stated as 775C>G in the paper which used the Latif sequence as reference) and c.241C>T (stated as 454C>T in the paper). Patient 1 was unaffected and had the wild-type allele. His spouse, patient 2, presented with pheochromocytoma and had both mutations. They had four children; one had a pheochromocytoma and died, two (patients 5 and 7) had both mutations and presented with pheochromocytomas, and one child (patient 6) was unaffected and carried neither mutation. Patient 7 had a child (patient 9) who also carried both mutations and presented with pheochromocytoma. In the other branch of the family, patient 3 who carried both mutations and presented with pheochromocytoma had a child with patient 4 who was unaffected. Their child (patient 8) carried both mutations and presented with pheochromocytoma. Patient 8 had two children; one who did not carry the mutation and was unaffected (patient 10) and another that carried both mutations but was disease-free (patient 11). DNA was isolated with whole blood and denaturing high-performance liquid chromatography (DHPLC) and dye terminator method on an ABI Prism 310 genetic analyzer (Applied Biosystems, Weiterstadt, Germany) were used for sequencing. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

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 E46* (c.136G>T) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V65).

PatientID: V48

KindredID: V48

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H115Q (c.345C>G)

MultipleGeneVariants: N/A

PMID: 9663592

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID: 4

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:0005584; HP:0002666; HP:0009711; HP:0001737 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Pheochromocytoma (1), Retinal capillary hemangioma (1), Pancreatic cysts (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

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

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. 2 patients were found to have the above mutation (c.472C>G). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was 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.

GroupID: 24A

DiseaseAssertion: VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 VHL patients with the given VHL mutation and manifestation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

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

GroupID: 12A

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.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

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. 5 patients were found to have the above mutation (c.548C>A). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) 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. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease .

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.R82P (c.245G>C) germline variant of the VHL gene was detected in a family (ID 12). Members 697, 752 and 2682 presented with moderate renal disease (RCC). Member 4321 presented with severe renal disease (RCC). Members 2062, 606, 607, 609, 444, 3974 and 2523 presented with unknown renal involvement. Member 5357 had no renal involvement. Member 5037 had mild renal disease and member 605 had moderate renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

PatientID: 5800

KindredID: 283

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: c.340+1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transition

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

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.Y175* (c.525C>G) germline variant of the VHL gene was detected in a family (ID 63). Member 2656 had unknown renal involvement. Members 2511, 4325, 2744 and 2668 presented with mild renal disease (RCC). Members 2588, 2746 and 4630 presented with moderate renal disease (RCC). Members 2060 and 2279 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

PMID: 15709172

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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

PatientID: 107

KindredID: 36

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.H110Pfs*49 (c.329delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H110PFS*49 (c.329delA)

MultipleGeneVariants: N/A

PatientID: 37

KindredID: 12

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 291

KindredID: 115

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband, patient 291, presented with a CNS hemangioblastoma at 27, and at 31 presented with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

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 3 Deletion (c.464-?_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 3 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. A male patient was confirmed for nonsense mutation in the VHL gene (c.217C>T; p.Gln73*). He was diagnosed with CNS haemangioblastoma at 66Y, retinal angioma at 66Y, renal cell carcinoma at 37Y, and multiple pancreatic cysts or tumours at 54Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336). It is likely that all three papers reported on the same individual.

PatientID: 141

KindredID: 52

Case: F, 69Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: c.464-1G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>C)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. One proband was genetically confirmed with this germline mutation: a 46 year old female from kindred #89 who presented with a renal cell carcinoma at that age. This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 259

KindredID: 100

Case: F, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 259, presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 28, and a retinal angioma at age 24. The proband's son, patient 260, was asymptomatic at the time of analysis.

CasePresentingHPOs: N/A

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

CaseHPOFreeText: The proband, patient 259, presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 28, and a retinal angioma at age 24.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 1-2 Deletion (c.1-?_463+?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 1-2 Deletion

MultipleGeneVariants: N/A

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.256C>G), which was found in 1 individual from Italy.


GroupID: 22

Case: Sex unknown, Age unknown, Italian

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.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

GroupID: 16

Case: Sex unknown, Age unknown, German

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.N131T (c.392A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351753944 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.392A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N131T (c.392A>C)

MultipleGeneVariants: N/A

PMID: 29616089

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

74 patients (38 males, 36 females; 24 with prior sequencing data) with pheochromoctyoma were first analyzed by denaturing high performance liquid chromatography (dHPLC). PCR of all exons of VHL was performed on leukocyte DNA extracted from stored blood samples, and those showing variance were sequenced. In addition, 35 positive controls were used to confirm this method. This patient was a positive control who has been previously sequenced (not referenced). One patient was found with the R167Q (c.500G>A) VHL mutation. No family history was mentioned or clearly stated of their phenotypes.

PatientID: 10

KindredID: 1

Case: M, 35Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0006770 (pheochromocytoma; hemangioblastoma; clear cell renal cell carcinoma)

CaseHPOFreeText: bilateral pheochromocytoma sized R: 3.0(cm), L: 1.0(cm); Grade 2 cystic clear cell renal cell carcinoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/TMEM127

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: See table 4 for SDHB information; See table 6 for TMEM127 information

MutationType: exon_loss_variant

CivicName: EXON 2-3 DELETION

MultipleGeneVariants: N/A

PMID: 32432044

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 44

KindredID: 44

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Retinal hemangioblastoma and renal cystic lesion.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Parents, siblings and nephew were negative for the mutation confirming that this variant was de novo in the proband. No phenotype details are noted for these family members.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000107; HP:0006770; HP:0010797; HP:0001732 (Renal cyst, Clear cell renal cell carcinoma, Hemangioblastoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.V155G (c.464T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621938, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.464T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V155G (c.464T>G)

MultipleGeneVariants: N/A

PatientID: 214

KindredID: 214

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transversion

CivicName: S65W(c.194C>G)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. Germline mutation c.-65_-55dup11 (mapped to c.-61_-51dup) was identified in prodand 221, 230 and 231. Proband 221 (12Y) presented with retinal capillary hemangioma. Proband 230 (40Y) presented with CNS hemangioblastoma. Proband 231 (9Y) presented with CNS hemangioblastoma. All three patients were previously published in PMID 17006605.

PatientID: 254

KindredID: 254

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

CasePresentingHPOs: HP:0009711; HP:0001732 (Retinal capillary hemangioma, Abnormality of the pancreas)

CaseHPOFreeText: Retinal hemangioblastoma and pancreatic cyst or tumor.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0000107; HP:0006770 (Hemangioblastoma, Pheochromocytoma, Renal cyst, Clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

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; deletion

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 351

KindredID: 351

Case: Sex Unknown, 40Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but no details provided.

CasePresentingHPOs: HP:0010797; HP:0000107 (Hemangioblastoma, Renal cyst)

CaseHPOFreeText: CNS hemangioblastoma and renal cystic lesion.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19464396

SupplementalData: Table S1, S2 and S3

Variant: p.I109Tfs*50 (c.326del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658820709, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.326del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: I109fs (c.326delT)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. This novel, missense mutation was found in a 16 yr old VHL patient with pheochromocytoma (index case 55). Variant was transmitted from a parent (both parents were analyzed) but it is unclear which parent was positive for the variant.

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. This de novo, missense mutation, c.233A>G, was found in 2 VHL patients. A 24-year-old patient had retinal capillary hemangioma, pancreatic lesions, and renal cysts (index case 152). The other patient, a 33-year-old, presented with hemangioblastomas of the central nervous system and pancreatic lesions (index case 45). This variant also potentially alters the stability of the beta domain of the VHL protein. There is strong evidence for pathogenicity because this variant is de novo in a patient with the disease and no family history.

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The R107Pfs*25 (c.314dup) germline variant of the VHL gene was found in a 16 year old patient (ID 225) presenting with CNS hemangioblastoma. The variant is noted as Familial (i.e. “transmission of the variant from a parent”). Sibling was analyzed but details are not provided. The variant was reported as c.314_315insC and was mapped to c.314dup. There is co-segregation of disease with mutation.

PatientID: 3

KindredID: 3

Case: Sex Unknown, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had family history of VHL disease. The patient’s aunt and her son had the same mutation, but no clinical manifestations. The patient’s mother, another aunt and her son had hemangioblastomas at age 30, 33, and 32, respectively, but died prior to genetic testing could be performed.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

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

CaseHPOFreeText: The patient presented with a hemangioblastoma at age 28, as well as renal cell carcinoma at age and abnormality of the pancreas at age 38.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This nonsense mutation was found in 2 unrelated families. One family of 3 had a asymptomatic 27-year-old female, a 27-year-old male with epididymal cystadenoma, and a 55-year old with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 10). The other VHL family had 2 individuals with hemangioblastomas of the central nervous system (proband no. 11).

PatientID: N/A (Case)

KindredID: 1

Case: M, 32Y0M, Thai (South Asian)

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880; HP:0030405 (cerebellar hemangioblastoma; pancreatic endocrine tumor)

CaseHPOFreeText: This male was diagnosed with VHL at 20Y when he was found to have a cerebellar hemangioblastoma. Abdominal CT obtained as part of routine surveillance demonstrated multiple cystic lesions with rim enhancement in the pancreas. 10 years later, he developed abdominal discomfort, and an abdomen CT showed multiple solid and cystic enhancing lesions involving the entire pancreas with a hypervascular mass at segment 7 of liver. Given radiological findings, he was diagnosed with malignant pancreatic neuroendocrine tumor (PNET) with liver metastasis, thereupon underwent total pancreactomy with wedge resection of the liver mass. Surprisingly, the histopathology revealed a serous cystadenocarcinoma in the pancreas measuring 28 x 11.5 x 7 cm and a 4.5 x 4.5 x 3 cm metastatic lesion in the liver with hepatic capsular invasion. 

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Genetic testing revealed a large deletion of exon 3 and poly A sites of VHL gene.

MutationType: exon_loss_variant

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 71Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father died of acute myeloid leukaemia at age 63. The patient had four children one of whom had the same VHL mutation as her and presented with breast cancer. That child had three sons all of whom carried the VHL mutation. Two of the sons were asymptomatic and one had renal cell carcinoma. The affected son also had a P2P mutation. See Figure 1 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P81S (c.241C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 42

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 registrants belonging to the same family (42) have the germline VHL deletion.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0000107; HP:0030393 (hemangioblastoma, retinal capillary hemangioma, pancreatic cysts, renal cyst, endolymphatic sac tumor)

GroupHPOFreeText: 4/5 members had hemangioblastomas, 1 had retinal capillary hemangiomas and renal cysts, 2 had pancreatic cysts, 2 had endolymphatic sac tumors, and 1 had an adnexal papillary tumor of probably mesonephric origin

GroupNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 deletion

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. This in-frame deletion variant (c.227_229delTCT) was detected in 2 VHL families: 24 and 25. Family no. 24 was a type 2 family with 1 patient with central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and epididymal cysts. They were identified as sporadic with their parents being excluded from having a germline mutation, although they were not available for DNA analysis. Family no.25 had 2 members with retinal hemangioblastomas and renal cell carcinoma, as well as 1 member with CNS hemangioblastoma. This was published in a future publication: PMID: 32179488.

GroupID: 14

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, two individual was suspected of VHL disease, but neither developed RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: This VHL patients did not present with retinal capillary hemangioma.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

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: Chr3(GRCh37): g.10183722G>C

MutationType: missense_variant; transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

GroupID: None

Case: Sex Unknown, 41Y0M, Dutch

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0005584; HP:0000107; HP:0001737 (Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 31087189

SupplementalData: N/A

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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this splice varaint in the VHL gene. The patient was 32Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. This cohort was published later in PMID 31087189.

PatientID: None (proband 10’s son)

KindredID: 10

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s father was found with hemangioblastoma diagnosed at 39Y, as well as retinal capillary hemangioma, renal cell carcinoma and pancreatic cysts diagnose at 57Y

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCC diagnosed at 30Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178R (c.533T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625261 https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L178R (c.533T>G)

MultipleGeneVariants: N/A

During the period from 2009 to 2012, 39 families with VHL disease were diagnosed with hereditary VHL disease at Peking University First Hospital Department of Urology were described as part of a broader study examining telomere length and anticipation. In these families, 19 families had two or more than two patients in two or more than two generations, including one family with obscure onset age. Therefore, a total of 57 patients with VHL disease from 18 families were enrolled in this study. Using peripheral blood and southern blotting, DNA sequencing was completed on the following patients. Family 3 involved two members with a c.280G>T change leading to a p.Glu94Stop protein change. The first member, a male, presented with hemangioblastoma at age 54 and renal cell carcinoma and pheochromocytoma at age 53. The second member, the proband’s son, presented with papillary cystadenoma of the epididymis at 23, renal cell carcinoma at 29, and pancreatic cysts at 29. Family 12 was additionally found with this mutation. This included a male proband found with hemangioblastomas at 31Y. His mother was also found with hemangioblastoma at 30Y, however she died before diagnosis; thus no DNA sample available. ACMG Evidence Code: 'PP4' because the patients' phenotypes and family histories are highly specific for VHL disease.

PatientID: 4

KindredID: 4

Case: F, 24Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history involved.

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F75Yfs*57 (c.222_223insT)

CaseProblemVariantFreeText: paper states 2 mismatched protein changes vs cDNA changes: c.223_224insT matches with p.F76Lfs*56. To get the given protein sequence they use: p.I75fs, the mutation should be c.222_223insT.

LegacyVariant: N/A

ClinVar: N/A

CAID: CA2499306953 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306953

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: F76Lfs*56 (c.224dup)

MultipleGeneVariants: N/A

PatientID: II:10

KindredID: 1

Case: F, Age Unknown (deceased), Jewish

DiseaseAssertion: VHL

FamilyInfo: This kindred of Jewish-Kurdish origin consisted of 3 generations of 25 members. 7 were clinically affected subjects with pheochromocytoma (5 of which had the confirmed mutation - I:1, II:2, II:4, II:7 and II:9, as the other 2, II:5 and II:10 were said to have passed due to complications of the disease - prior to any genetic testing), and 4 others were carriers, or pre-symptomatic (III:1, III:3, III:7 and III:12). Subject 11:7 developed a cerebellar hemangioblastoma 25 yr after his initial diagnosis of pheochromocytoma, leading to the clinical diagnosis of VHL in the kindred.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: patient had unilateral pheochromocytoma. She was said to have died of complications of the disease, and although genotype was not established prior, it is assumed that she carried the same VHL mutation

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 33471715

SupplementalData: N/A

Variant: p.V166F (c.496G>T) [assumed]

LegacyVariant: p.V166F (c.709G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

VariantEvidence: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 195

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Paper states familial VHL

CasePresentingHPOs: unknown

CaseHPOFreeText: Patient had VHL, but no specific phenotypes were described

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: exon 3 deletion (c.464-?_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 3 Deletion 

MultipleGeneVariants: N/A

PatientID: 22

KindredID: 22

Case: 13Y0M, Sex Unknown, Argentinian

DiseaseAssertion: hemangioblastoma

FamilyInfo: No family history

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

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

CaseNotHPOs: N/A

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

This paper presents the first case of VHL associated with acute myeloid leukemia. The patient is reported to have the 407 C/T (F136S) mutation of the VHL gene. He was admitted at the time of the study (38Y) with significant anemia, increased number of leukocytes and pneumonia. He had a history of renal cell carcinoma and a hemangioblastoma in his brainstem (medulla oblongata). Three years later he had recurrent renal cell carcinoma followed by a massive hematuria, dilated cardiomyopathy, complex valves defect, severe central sleep apnea, anemia, leukocytosis, moderate thrombocytopenia and erosive gastritis. Physical examination revealed a heart murmur and splenomegaly (confirmed by ultrasound). Prolonged bone marrow aplasia resulted in severe interstitial pneumonia and septicemia. The patient died from respiratory failure. The autopsy revealed a pulmonary edema, massive hyperemia of the left lower lobe with pneumonia confluens.

GroupID/ KindredID: 91CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 91CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158V (c.472C>G)

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

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 (S111fs (c.331delA)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3669NCI. It was reported in the paper as c.544delA 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: 110CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 110CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, ithout 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.G57Rfs*75 (c.167_168insA)

LegacyVariant: (c.380insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA916084344 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.167_168insA

gnomAD: N/A

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

MutationType: plus_1_frameshift_variant

CivicName: G57fs (c.167_168insA)

MultipleGeneVariants: N/A

PatientID: 16

KindredID: 16

Case: F, 50Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0010797 (Renal neoplasm, Hemangioblastoma)

CaseHPOFreeText: Patient 16 had genetic testing and was found to have a germline mutation c.286C>T (Gln96*).

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96* (c.286C>T)

LegacyVariant: c.499C>T

CaseProblemVariantFreeText: N/A

ClinVar: 428804, https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

CAID: CA351750811

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: Q96* (c.286C>T)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: 31Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs:  HP:0010797; HP:0005584; HP:0002666 (hemangioblastoma, renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: CNS hemangioblastoma first presenting at 24Y, RCC and pheos at 31Y

CaseNotHPOs: HP:0009715 (Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

ArticleReferenceSequence: NM_000551.3

GenotypingMethod: Paired whole-exome sequencing (WES), Sanger sequencing, and immunohistochemistry (IHC)

SamplingMethod: peripheral blood

PatientID: None (proband’s uncle)

KindredID: 1

Case: M, Age unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Recorded family history of VHL disease, with the patient’s 4 sisters, mother, and brother suffering from the disease. 5 of these individuals in the family had succumbed to cerebral hemangioblastomas. No mutation was stated. The 34Y old proband (nephew) had cerebellar hemangioblastoma, renal cell carcinoma and pancreatic endocrine tumour and a confirmed c.473T>C mutation.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: unknown

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: N/A

CivicName: N/A - (L158P (c.473T>C))

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 10

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 2 members of this family presented with the c.712C>T/c.499C>T germline variant of the VHL gene. ID 3 presente with CNS hemangioblastoma, retinal angioma and renal cell carcinoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

20 unrelated VHL families were retrospectively identified in SickKids Genetics and Cancer Genetics Program SHIRE genetics database, with data entered between 30 August 1984 and 8 August 2016. Family 9 had one patient with the missense mutation c.257C>T in the VHL gene (legacy notation c.470C>T). The proband (male) was diagnosed with CNS hemangioblastoma at 16Y and was 23Y at the end of the study. This patient was later published in 31368132- updated phenotypes available.

PatientID: 17 (Cousin)

KindredID: 1

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. ID 35 was asymptomatic. IDs 28, 2, 6, 1 (proband) 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: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a Pheochromocytoma at age 8.

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

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: 1 (Proband)

KindredID: 3

Case: M, 3Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 3 members of this family were genetically confirmed to be carriers of a germline partial deletion of exon 2 of the VHL gene. ID 8 presented with CNS hemangioblastoma and ID 2 presented with retinal angioma and pancreatic abnormality. ID 16 presented with a retinal angioma (33Y), CNS hemangioblastoma at (32Y) and died at age 42. ID 16 was stated as having the germline variant but this was inferred from family/personal history and was not genetically confirmed.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: Exon 2 Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Partial deletion of Exon 2)

MultipleGeneVariants: N/A

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The L178P (c.533T>C) germline mutation was found in a VHL type 1 patient presenting with CNS hemangioblastoma, retinal angioma and renal cell carcinoma (family ID 34). This family was previously reported in PMID 8634692.

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The E173Rfs*29 (c.516del) germline mutation was found in a VHL type 1 patient presenting with CNS hemangioblastoma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma (family ID 105).

Screening of 3 patients affected with familial PC for mutations in the RET proto-oncogene (mutations related to MEN 2 syndrome) and the VHL tumor suppressor gene (mutations related to VHL disease) with the use of PCR, SSCP, heteroduplex analysis, and direct sequencing, revealed missense VHL gene mutations. Please note that there was no clinical diagnosis of VHL disease. This missense mutation c.499C>T was found in a Polish family with 3 siblings (two male siblings and their mother) with no evidence of RET; the older brother presented with unilateral pheochromocytoma at 15Y, the younger brother presented with bilateral pheochromocytoma at 11Y, and the mother presented with bilateral pheochromocytoma at 41Y. Additional phenotypic information was not provided. Please note that the paper states the mutation as c.712C>T because it uses a legacy reference sequence.

PatientID: 8

KindredID: 8

Case: F, 49Y0M, Korean

DiseaseAssertion: Assumed VHL

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0006880 (adrenal pheochromocytoma, renal cell carcinoma, cerebellar hemangioblastoma)

CaseHPOFreeText: The patient presented with adrenal pheochromocytoma. She also had other tumours, including renal cell carcinoma and cerebellar hemangioblastoma (see table 3).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

PatientID: II-5

GroupID/ KindredID: 6

Case: Age unknown (deceased), M, Chinese

DiseaseAssertion: hemangioblastoma

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

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 10

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 4 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0005584; HP:0001732; HP:0010797; HP:0009711 (Renal cell carcinoma, abnormality of the pancreas, hemangioblastoma, retinal capillary hemangioma)

GroupHPOFreeText: 2 members had renal cell carcinoma, 1 had an abnormality of the pancreas, 1 had a CNS hemangioblastoma, and 1 had retinal capillary hemangioma

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No family members appeared to have the above manifestation.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.P86L (c.470C>T)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 15

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 4 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: 2 members had CNS hemangioblastomas, 2 had a retinal angiomas, 2 had RCC, 1 had a pancreatic abnormality

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No family members appeared to have the above manifestation.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117* (c.351G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.W117* (c.564G>A)

ClinVarID: N/A

CAID: CA351753679 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.351G%3EA

gnomAD: 0.000003976 https://gnomad.broadinstitute.org/variant/3-10188208-G-A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W117* (c.351G>A)

MultipleGeneVariants: N/A

PatientID: IV-12

KindredID: 2

Case: M, 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

Of 14 caucasian 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 11, age 19, was diagnosed only with retinal vascular proliferation. She was found to carry the R167Q (c.500G>A) mutation. Presurgical and postsurgical optical coherence tomography in patient 11 demonstrated the fibrovascular complex as a hyperreflective layer that was limited to the vitreoretinal surface. There was traction on the underlying retinal tissue, resulting in thickening and obliteration of the foveal contour. Postsurgically, excision of the complex restored the overall shape of the foveal contour, leaving behind only a small disruption in the outer retinal lamination and a small residual macular epiretinal membrane. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: None

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0006748, HP:0100827, HP:0001894, HP:0009713, HP:0031496 (Adrenal pheochromocytoma, lymphocytosis, thrombocytosis, spinal hemangioblastoma, mucinous cystic neoplasm of the pancreas)

CaseHPOFreeText: At age 45 the patient was admitted for 2-week history of fatigue and muscle weekness. MRI showed bilateral chronic infarcts resulting from multiple cryptogenic strokes in his past medical history. Blood tests revealed unexplained lymphocytosis and thrombocytosis.The patient was found to have bilateral adrenal phoechromocytomas, hemangioblastomas in the spinal cord at T11 and in the cauda equina at L2, and multiple intraductal papillary mucinous neoplasms.

CaseNotHPOs: HP:0005584, HP:0030405 (renal cell carcinoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

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 8) was found to carry the mutation c.350G>C in exon 2 of the VHL gene. The proband presented with hemangioblastoma at age 18 and renal cell carcinoma and abnormality of the pancreas at age 24. The patient had negative VHL family history. This patient was previously published in 29330336.

PatientID: 15

KindredID: 6

Case: F, 22Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 1 other member of this family presented with the same variant. Patient 16 (Gen 2) presented with bilateral pheochromocytoma.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

CaseHPOFreeText: Sympathetic paraganglioma and bilateral pheochromocytoma. Age of onset for pheochromocytoma and paragangliomas is stated as 11Y and 22Y but it is not clear which age pertains to which phenotype.

CaseNotHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0030405 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma, Pancreatic endocrine tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

PMID: 29124493

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: None

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s daughter, age 27, presented with two right renal masses and several pancreatic cysts at 22Y. The patient’s brother, age 38, presented with unilateral ccRCC. Both the patient’s daughter and brother were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0006770; HP:0001737 (Clear cell renal cell carcinoma, pancreatic cysts)

CaseHPOFreeText: The patient presented with right ccRCC and pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: None(c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

Twelve patients with hereditary non-SDHx head and neck paragangliomas were analyzed. Eleven of the twelve patients were found to carry germline mutations in the VHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. A total of five patients in this cohort were found to harbour the p.Tyr98His germline mutation of the VHL gene. As well as one patient from literature (previously published in 9880225). In family 1, the proband (case 1) was a 7 year old male diagnosed with malignant extra-adrenal pheochromocytoma of the left retroperitoneum with regional lymph node metastases and treated with resection of the primary tumor, lymphadenectomy, and chemotherapy. At age 9, he presented with a local reocurrance which was treated with resection and external radiotherapy of 20Gy. At age 13, he presented a right adrenal pheochromocytoma which was resected. At age 15 a left carotid body tumor was clinically detected and removed, but recurred at age 16 and again was resected. At age 17, a pheochromocytoma at the renal pelvis was diagnosed by MRI and resected. At age 18, he was disease free except for a lesion in the L1 vertebral body suggestive of hemangioma or pheochromocytoma. His mother was asymptomatic but had the mutation. His cousin had the mutation and presented with a pheochromocytoma. His aunt also had the mutation and a history of retinal hemangioblastomas. The fifth patient with this mutation (case 10), an unrelated 34 year old female, presented with no personal or family history of VHL and persistent pharyngeal discomfort. MRI demonstrated a 4cm tumor in the parapharyngeal space. The tumor was removed, and histology revealed a paraganglioma. Postoperatively, she had Horner’s syndrome and a transitory hypoglossal paresis. At age 46, bilateral adrenal pheochromocytoma and a paraaortic paraganglioma were removed. Later, her niece was diagnosed with a pheochromocytoma, and her brother suffered from pheochromocytoma, renal cell carcinoma, and retinal hemangioblastomas. The proband’s mother was then found to have pheochromocytoma. Case 23 was from the literature and was a female presenting with pheochromocytoma, paraganglioma of head and neck, retinal capillary hemangioma and pancreatic cysts. The patient had a positive family history.

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 missense variant p.P154L(c.461C>T) was identified in patient #14. This mutation was noted as c.674C>T in the paper due to a difference in reference transcript used (see Table S1). No family information is available for this patient.

Case1: 13 year old female

DiseaseAssertion: LVNC

FamilyInfo: No family history of cardiac disease

ParentalTesting:

CasePresentingHPOs: HP:0011664. HP:0002094. HP:0001279. HP:0031295

CaseHPOFreeText:Left Ventricular noncompaction, Dyspnea (shortness of breath), Fainting, Left atrial enlargement

CaseNotHPOs:HP:0000929. HP:0001712

CaseNotHPOFreeText:Abnormal skull morphology, left ventricular hypertrophy

CasePreviousTesting:

Genotyping Method:Next-Generation Sequencing (NGS)

FunctionalAnalysis:

Variant:c.575G>A

ClinVar:12424

CAID:CA021957

gnomAD:

AdditionalInfo:

PMID: 30279906

Gene: TNNI3

HGNC ID: 11947

PMID: 20641121

Gene: MYL3

HGNC ID: HGNC:7584

Case1:Female diagnosed at 28

DiseaseAssertion:HCM, ASH, LVEF

FamilyInfo:Sister with HCM, ASH, and mid-LV cavity obstruction

ParentalTesting:

CasePresentingHPOs:HP:0001639, HP:0001670, HP:0034314, HP:0001279

CaseHPOFreeText:Hypertrophic cardiomyopathy, Asymmetric Septal Hypertrophy, Abnormal Left Ventricular Ejection Fraction, Syncope

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

Genotyping Method:Not detailed

FunctionalAnalysis:MYL3 A57G

Variant:c.170C>G (p.Ala57Gly)

ClinVar:31780

CAID:CA013589

gnomAD:

AdditionalInfo: