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: 1

KindredID: 1

Case: F, 44Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient has a notable family history. Her eldest brother had multiple RCCs in both kidneys, bilateral cerebellar hemangioblastomas, and pheochromocytoma in his left adrenal gland (see Patient 2). Her daughter also underwent cortex-sparing adrenalectomies for bilateral pheochromocytomas as well as hemangioblastoma resection in her left cerebellum at age of 19 years, although no testing for VHL was stated.

CasePresentingHPOs: HP:0006748, HP:0030405, HP:0006880, HP:0000107, HP:0005584 (adrenal pheochromocytomas, pancreatic endocrine tumour, cerebellar hemangioblastoma, renal cyst, renal cell carcinoma)

CaseHPOFreeText: Patient diagnosed at age 29 with bilateral pheochromocytomas when she presented with severe hypertension and two large masses (greater than 6 cm) in her bilateral adrenal glands. At 38 years old, she underwent a resection for a mass found on her pancreas, with pathological analysis of the mass revealing a pancreatic neuroendocrine tumor. At 42 years old, a follow-up CT scan revealed two heterogeneous contrast-enhanced masses, one on the right kidney and one on the left adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAiD: CA16621914 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 41

KindredID: 14

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and multiple pancreatic cysts/ tumors at age 44.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.S80Ifs*79 (c.239del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189245; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239del)

MultipleGeneVariants: N/A

PatientID: 47

KindredID: 15

Case: F, 22Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (oatient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52.

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

CaseHPOFreeText: The proband's niece 1 (patient 47) had a retinal angioma and renal cell carcinoma at 22.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0002666; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, Hemangioblastoma)

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: p.S80Tfs*77 (c.239_245del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189246; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239_245del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239_245del)

MultipleGeneVariants: N/A

GroupID/ KindredID: 39CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 39CE. 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.S80N (c.239G>A)

LegacyVariant: p.S80N (c.452G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 1070179 https://www.ncbi.nlm.nih.gov/clinvar/variation/1070179/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL2

Case: M, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had LOH found in the BAC array CGH data.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: Father (of proband)

KindredID: 7

Case: M, 80Y0M, Chinese

DiseaseAssertion: renal cell carcinoma

FamilyInfo: Positive - His 2 children both had the same germline mutation. This first child (proband; sex unknown) had hemangioblastoma first presenting at 55Y, and their second child (son) was asymptomatic.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: asymptomatic upon genetic testing, but screening of VHL tumours after genetic testing revealed a left RCC with lung metastasis at 80Y

CaseNotHPOs: HP:0002666; HP:0009715; HP:0010797 (pheochromocytoma, Papillary cystadenoma of the epididymis, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: None (Cousin 2)

KindredID: G

Case: Sex Unknown, 38Y0M, Hungarian

DiseaseAssertion: Assumed VHL

FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

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

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 38, pheochromocytoma at age 39 and retinal hemangioblastoma at age 29. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as S80I and cDNA change was mapped to c.239G>T.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: IV-16

KindredID: 1

Case: M, 16Y0M, Hungarian

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient had two unaffected siblings who did not carry the mutation. The patient's father (III-8) carried the mutation and had brain hemangioblastoma, pheochromocytoma, and retina hemangioblastoma. His paternal aunt (III-7) harboured the same mutation and had a brain hemangioblastoma and retina hemangioblastoma. Her children, this patient's cousins, also harboured the mutation and had clinical presentations of VHL. His other paternal aunt (III-6) carried a different VHL mutation, Pro25Leu, but was asymptomatic. The patient's paternal grandmother (II-5) also harboured the same mutation and presented with renal cell carcinoma. This patient's great aunt (II-1) carried two different VHL mutations; the Ser80Asn and Pro25Leu but herself was asymptomatic. She passed the Ser80Asn mutation to her daughter, the proband (III-1), who had renal cell carcinoma, brain hemangioblastoma, and pheochromocytoma. Refer to figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80N (c.239G>A)

LegacyVariant: p.S80I (c.239G>A) *author mistake

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70046108 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

PatientID: IV-13

KindredID: 1

Case: F, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The patient had an affected brother (IV-14) who carried the Ser80Asn mutation and presented with pheochromocytoma and retina hemangioblastoma. The patient's mother (III-7) carried the same mutation and had a brain hemangioblastoma and retina hemangioblastoma. The uncle (III-8) harboured the same mutation and had brain hemangioblastoma, pheochromocytoma, and retina hemangioblastoma. He had three kids, out of which only one carried the mutation but was asymptomatic (IV-16). The patient's grandmother (II-5) also harboured the same mutation and presented with renal cell carcinoma. This patient's great aunt (II-1) carried two different VHL mutations; the Ser80Asn and Pro25Leu but herself was asymptomatic. She passed the Ser80Asn mutation to her daughter, the proband (III-1), who had renal cell carcinoma, brain hemangioblastoma, and pheochromocytoma. Refer to figure 1 for pedigree.

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

CaseHPOFreeText: The patient presented with brain hemangioblastoma at age 22, retina hemangioblastoma at age 23, and renal cysts at age 20.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80N (c.239G>A)

LegacyVariant: p.S80I (c.239G>A) *author mistake

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70046108 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A