PatientID: 47 (Uncle)

KindredID: 18

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (30 and 42Y) and retinal angioma (26Y). Patient died at 39Y.

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial 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: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 132

KindredID: 50

Case: F, 45Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 132) had multiple family members who were unconfirmed with the mutation. Her brother 1 (patient 133) had a CNS hemangioblastoma at 29, and renal cell carcinoma and multiple pancreatic cysts/tumors at 48; however no DNA sample was available for testing. Her brother 2 (patient 134) had a CNS hemangioblastoma at 27, but passed away before he could be genetically confirmed with the mutation. Similarly, her father (patient 135) had a CNS hemangioblastoma at 25, but passed away before he could be genetically confirmed.

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

CaseHPOFreeText: The proband's nephew (son of brother 2) (patient 233) had a renal cell carcinoma at age 30.

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: p.Q145Yfs*27 (c.433_437del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131796, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131796

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: Q145fs (c.433_437delCAGCC)

MultipleGeneVariants: N/A

PatientID: N/A (case)

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0006765 (Hemangioblastoma; Retinal capillary hemangioma; Chondrosarcoma)

CaseHPOFreeText: Patient presented at 48Y with pain in her left arm. She was diagnosed with VHL at 25Y. She had surgery for CNS HB at ages 26, 28, 39, and 45Y. She also had retinal HB and underwent a coagulation procedure at 26Y. A lytic lesion was found in the left distal ulna (clear cell chondrosarcoma)

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemnagioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: An unspecified gene panel analysis was performed, where no additional mutations were found (except for a non-pathogenic, variant of the ATM gene (c.1810C>T; p.(Pro604Ser))).

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: Loss of wild type VHL during tumour development.

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 8 (Mother)

KindredID: 3

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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 2 presented with retinal angioma and pancreatic abnormality. ID 1 was asymptomatic. 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: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The patient presented with CNS hemangioblastoma (26Y and 40Y).

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

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

PatientID: 218

KindredID: 81

Case: M, 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's sister (the proband) had the same germline mutation, and presented with a CNS hemangioblastoma at 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.

CasePresentingHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 20, and a pheochromocytoma at age 26.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

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.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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 122

KindredID: 43

Case: F, Age 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 19, and multiple pancreatic cysts/tumors at 26.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711 (Renal cell carcinoma, 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: p.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753664; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: F, 26Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history of VHL.

CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.

CasePresentingHPOs: HP:0000618; HP:0009711; HP:0010797; HP:0002668 (blindness, retinal capillary hemangioma, hemangioblastoma, paraganglioma)

CaseHPOFreeText: At 15Y she presented with loss of visual acuity, leading to the diagnosis of bilateral retinal hemangioblastomas (treated with laser and cryotherapy), with the outcome of unilateral blindness. The patient was then operated 3 times for CNS hemangioblastomas between ages 18 and 24. At age 26, she presented with a palpable lateral neck mass. CT of the head and neck revealed a 3-cm carotid body tumor (paraganglioma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T105P (c.313A>C)

LegacyVariant: p.T105P

CaseProblemVariantFreeText: As the publication only provides the p., the mutation was deduced to p.T105P (c.313A>C)

ClinVarID: 496055 https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: T105P (c.313A>C)

MultipleGeneVariants: N/A