A case report of a 46Y old Chinese male VHL patient presenting with multiple clear cell renal cell carcinoma at the age of 43 is described. Additional manifestations included renal and pancreatic cysts. Molecular analysis through peripheral blood confirmed the presence of the (c.302T>G) mutation. Family history showed a clinical diagnosis of VHL in the father and sister who had the following manifestations: CNS hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumor, and renal cysts. See PMID: 24112165 for more information on this family.

PatientID: 1

KindredID: 1

Case: M, 46Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: known family history of VHL - His father, who had neoplasm and cyst in both kidneys, died of HB-CNS at 50 years old; and his sister was found to have neoplasm in both her pancreas and kidney. Explicit mutations or testing was not mentioned. In PMID: 24112165, these two members are confirmed with the mutation.

CasePresentingHPOs: HP:0006770; HP:0000107; HP:0001737; HP:0001407 (clear cell carcinoma; kidney cysts; pancreatic cysts; hepatic cysts)

CaseHPOFreeText: discovered to have signal abnormalities in his left kidney, liver and pancreas in a computed tomography (CT) evaluation - 2 tumors, one upper and one middle pole of the left kidney, as well as a cyst was found. At 43Y he was diagnosed with ccRCC in the right kidney via a hematuria and right-side lumbago.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24112165

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>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 (L101R (c.302T>G)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 23BMS. It was reported in the paper as c.515T>G 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.

Germline mutations were found in 20 Brazilian, VHL probands and their families. The L101R (c.302T>G) germline missense mutation was found in 2 affected family members with hemangioblastomas of the central nervous system (VHL family 5).

PatientID: III:2

KindredID: 1

Case: F, 8Y0M, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: large family history of VHL was tested - 3 members found. The patients mother and uncle had the same mutation and RCC, hemangioblastoma, and renal and pancreatic cysts

CasePresentingHPOs: N/A

CaseHPOFreeText: No clinical manifestations at the time of the publication

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 22398592

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

PatientID: 22

KindredID: 22

Case: F, 26Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: Multiple or bilateral CNS hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351751004

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 23BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 23BMS. 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.L101R (c.302T>G)

LegacyVariant: p.L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T>G

gnomAD: N/A

VariantEvidence: N/A

MutationType: frameshift_variant; transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

GroupID: 5

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 2 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

GroupHPOFreeText: CNS hemangioblastoma (2/2 affected members).

GroupNotHPOs: HP:0002894; HP:0009711; HP:0002666; HP:0005584; HP:0009726 (Neoplasm of the pancreas, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma, Renal neoplasm)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

PatientID: 2 (II:2)

KindredID: 1

Case: F, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: large family history of VHL was tested - 3 members found. The patient's brother and her daughter had the same mutation - Her brother (patient 1) was diagnosed with spinal hemangioblastoma, and at 43Y he was diagnosed with ccRCC in his right kidney

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0000107; HP:0001737 (hemangioblastoma, clear cell renal cell carcinoma; renal cysts; pancreatic cysts)

CaseHPOFreeText: had cerebellum hemangioblastoma at 38Y and a neoplasm of both kidneys at 40Y, as well as ccRCC, renal and pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 22398592

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A