GroupID: 13

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 39.0Y +/- 13.1Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 7 members total were described, and phenotypic information was given for this group.

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

GroupHPOFreeText: 5 of the 7 members presented with CNS hemangioblastoma (with a mean age of 34.2Y), retinal capillary hemangioma in 1 member at 26Y, renal cell carcinoma in 3 members (at the mean age of 36.7Y), pancreatic cysts in 2 members (at the ages of 32 and 38Y)

GroupNotHPOs: HP:0002666; HP:0009715 (pheochromocytoma, papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No patients presented with pheochromocytoma or a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament)

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336; 28388566

SupplementalData: N/A

Variant: p.I151S (c.452T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223215 https://www.ncbi.nlm.nih.gov/clinvar/variation/223215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: I151S (c.452T>G)

MultipleGeneVariants: N/A

PatientID: 128

KindredID: 48

Case: M, Age 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband had two family members who passed away before they could be confirmed with the mutation, but presented with VHL disease phenotypes. His father (patient 129) presented with renal cell carcinoma at age 58, and his daughter (patient 130) presented with a CNS hemangioblastoma at 13.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 32, renal cell carcinoma and multiple pancreatic cysts/tumors at 38, and pheochromocytoma at 40.

CaseNotHPOs: HP:0009711 (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.L135* (c.404T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754021; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L135* (c.404T>A)

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 13

Case: M, 44Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Son and brother presented with the same VHL variant. Son is asymptomatic. Brother presented with CNS hemangioblastoma at 29Y, retinal hemangioblastoma at 52Y, bilateral RCC at 43Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 43Y and bilateral renal cysts at 43Y. Nephew presented with CNS hemangioblastoma at 22Y, retinal hemangioblastoma at 18Y, bilateral RCC at 29Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 18Y but was not genetically confirmed.

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

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

CaseHPOFreeText: CNS hemangioblastoma at 32Y, retinal hemangioblastoma at 44Y, bilateral RCC at 44Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 41Y. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0000107; HP:0002666 (Renal cyst, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: 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

PatientID: P1

KindredID: 1

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s father, age 45, presented with right ccRCC and pancreatic cysts. The patient’s uncle, age 38, presented with unilateral ccRCC. Both the patient’s father and uncle were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0009726; HP:0001737 (Renal neoplasm, pancreatic cysts)

CaseHPOFreeText: The patient presented with two right renal masses and several pancreatic cysts at 22Y.

CaseNotHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, pheochromocytoma)

CaseNotHPOFreeText: Full VHL phenotyping with brain and spine MRI, abdominal CT, biochemical examination for pheochromocytoma, and ophthalmologic assessments did not reveal any additional VHL manifestations.

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (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

PatientID: 1

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her two sons and her father had the same VHL mutation.

CohortInfo:Three patients with endolymphatic sac tumors were studied.

CasePresentingHPOs: HP:0001737, HP:0002666, HP:0030393, HP:0009713 (pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, spinal hemangioblastoma)

CaseHPOFreeText: She presented with pancreatic cysts and pheochromocytoma at age 32. She experienced headache and dizziness and a temporal bone mass consistent with an ELS tumor was found on brain MR imaging. A preoperative audiogram showed no hearing function and she underwent a left transcochlear approach and resection of the tumor. The pathological diagnosis was consistent with an ELS tumor. She was later found to have a spinal hemangioblastoma that was resected and included in this study.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: The paper describes the mutation as "C-to-A transversion at position −1 on the exon 3 splice acceptor sequence in the VHL gene"

ClinVar: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 142

KindredID: 52

Case: F, 36Y0M, 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 sister 1 (patient 142) had a CNS hemangioblastoma at 31, and multiple pancreatic cysts/tumors and renal cell carcinoma at 36.

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

PatientID: 98

KindredID: 33

Case: M, 43Y0M, 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:0009711; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband's 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.

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

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: 217

KindredID: 81

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's brother had the same germline mutation, and presented with a CNS hemangioblastoma at 20, and a pheochromocytoma at 26. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.

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

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33.

CaseNotHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, 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.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