PatientID: 277

KindredID: 108

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 277, presented with a CNS hemangioblastoma at age 16, retinal angioma a 20, and renal cell carcinoma at 28. Their father who passed away before diagnosis presented with a CNS hemangioblastoma at 48.

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

CaseHPOFreeText: The proband, patient 277, presented with a CNS hemangioblastoma at age 16, retinal angioma a 20, and renal cell carcinoma at 28.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732 (Pheochromocytoma, 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: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 109

KindredID: 37

Case: M, 20Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 19, renal cell carcinoma and multiple pancreatic cysts/tumors at 20.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as 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.S111Tfs*48 (c.332delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189247; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.332delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S111fs (c.332del)

MultipleGeneVariants: N/A

PatientID: 97

KindredID: 33

Case: M, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 97) presented with a CNS hemangioblastoma at 37, retinal angioma at 20, and renal cell carcinoma and multiple pancreatic cysts/tumors at age 29. Their brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

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:0002666 (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.P97Afs*35 (c.287_288insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420510, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.287_288insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P97Afs*35 (c.287_288insA)

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: 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

PatientID: II-1

KindredID: Family B

Case: M, 23Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Family positive pedigree showing patient’s father with RCC and CNS hemangioblastoma; as well as 2 sisters with CNS/spinal and retinal hemangioblastomas

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

CaseHPOFreeText: underwent surgery for multiple CNS hemangioblastomas at the age of 15, and at the same age multiple peripheral retinal hemangioblastomas were found in his right eye, which were treated successfully with laser photocoagulation and cryotherapy. At the age of 20, he developed a large peripheral retinal hemangioblastoma in his left eye, which was treated successfully with cryotherapy.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79P (c.236G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351749311 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.236G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R79P (c.236G>C)

MultipleGeneVariants: N/A