PatientID: None

KindredID: S-FPH1

Case: Sex Unknown, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: 2 affected individuals in this family. Pheochromocytoma is noted as familial.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Family diagnosed with VHL type 2C.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236, https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: S-FPH1

KindredID: S-FPH1

Case: F, 60Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: 2 affected individuals in this family. Pheochromocytoma is noted as familial.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma. Diagnosed with VHL type 2C.

CaseNotHPOs: HP:0005584; HP:0010797 (Renal cell carcinoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236, https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: 39

KindredID: 39

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: patient had pheochromocytoma/paraganglioma (recorded here as a neuroendocrine neoplasm)

CaseNotHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 26

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0030405; HP:0100634 (hemangioblastoma, pancreatic neuroendocrine neoplasm, Neuroendocrine neoplasm)

CaseHPOFreeText: patient had CNS hemangioblastoma, pancreatic neuroendocrine neoplasm and pheochromocytoma/paraganglioma (recorded here as a neuroendocrine neoplasm)

CaseNotHPOs: HP:0006770; HP:0009711; HP:0030421 (clear cell renal cell carcinoma, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were reviewed. Peripheral blood leukocytes were isolated and directly sequenced. 1 patient presented with the c.250G>T/p.Val84Leu germline variant of the VHL gene. Patient 16, 60Y female previously published in PMID 16142346, presented with multiple pheochromocytomas and a positive family history for VHL. She was diagnosed with VHL Type 2C.

74 patients (38 males, 36 females; 24 with prior sequencing data) with pheochromoctyoma were first analyzed by denaturing high performance liquid chromatography (dHPLC). PCR of all exons of VHL was performed on leukocyte DNA extracted from stored blood samples, and those showing variance were sequenced. These patients had presented with clinical features and/or family history suggestive of a germline mutation, leading to their referral for genetic testing. 2 patients found with the V84L (c.250G>T) VHL germline mutation were listed.
 No family history was mentioned.

PatientID: None

KindredID: 2

Case: age, sex, ethnicity unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

Screening of 3 patients affected with familial PC for mutations in the RET proto-oncogene (mutations related to MEN 2 syndrome) and the VHL tumor suppressor gene (mutations related to VHL disease) with the use of PCR, SSCP, heteroduplex analysis, and direct sequencing, revealed missense VHL gene mutations. Please note that there was no clinical diagnosis of VHL disease. This missense mutation c.250G>T was found in a Welsh family with 2 siblings (one male and one female) with no evidence of RET; the brother presented with bilateral pheochromocytoma at 11Y and the sister presented with bilateral pheochromocytoma at 17Y. An asymptomatic parent was also documented. Additional phenotypic information was not provided. Please note that the paper states the mutation as c.463G>T because it uses a legacy reference sequence.

PatientID: None

KindredID: A

Case: Gender Unknown, Age Unknown, Welsh

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient had two sons and a daughter; of these three children, one son carried the mutation and presented with bilateral pheochromocytoma at 11Y, and one daughter carried the mutation and presented with bilateral pheochromocytoma at 17Y.

CasePresentingHPOs: Asymptomatic

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L(c.250G>T)

LegacyVariant: p.V155L(c.463G>T)

CaseProblemVariantFreeText: bandshift in exon 1 and genomic sequencing indicated a G>T transversion at nucleotide 463, substituting a valine for leucine at codon 155 (V155L). Leading to NM_000551.3:p.V84L(c.250G>T)

ClinVarID: 2236, http://www.ncbi.nlm.nih.gov/clinvar/variation/2236

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L(c.250G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: A

Case: F, 17Y0M, Welsh

DiseaseAssertion: Pheochromocytoma

FamilyInfo: The patient had a brother that presented with bilateral pheochromocytoma at 11Y. The patient also had an asymptomatic parent.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 17Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L(c.250G>T)

LegacyVariant: p.V155L(c.463G>T)

CaseProblemVariantFreeText: bandshift in exon 1 and genomic sequencing indicated a G>T transversion at nucleotide 463, substituting a valine for leucine at codon 155 (V155L). Leading to NM_000551.3:p.V84L(c.250G>T)

ClinVarID: 2236, http://www.ncbi.nlm.nih.gov/clinvar/variation/2236

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L(c.250G>T)

MultipleGeneVariants: N/A

Of 16 patients presenting with clinical VHL features that underwent genetic testing, one presented with the c.250G>T mutation of the VHL gene (stated as c.463G>T in the paper which used the Latif sequence as reference). Peripheral blood lymphocytes were collected and products of the polymerase chain reaction performed on this sample were analyzed with single-stranded conformational polymorphism analysis (SSCP), PCR sequencing and Southern analysis. This missense mutation was confirmed using restriction fragment length polymorphism or allele-specific oligonucleotide analysis. This patient has a family history of multiple tumor types indicative of VHL disease. The patient presented with a retinal angiomata, hemangioblastoma and pheochromocytoma.

PatientID: None

KindredID: Family C

Case: M, 54Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: There was no family history of VHL disease or familial pheochromocytoma. Her parents (mother age 85, father age 79) were asymptomatic and were not available for DNA testing. A 58-year-old maternal half-brother was tested and did not carry the mutation.

CasePresentingHPOs: HP:0006748, HP:0000107, HP:0009713 (adrenal pheochromocytoma, renal cyst, spinal hemangioblastoma)

CaseHPOFreeText: The patient had bilateral pheochromocytoma. A small vascular lesion was identified by a screening MRI, which that authors of the papers assumed could possibly a spinal hemangioblastoma,

CaseNotHPOs: None

CaseNotHPOFreeText: No other central nervous system abnormalities were detected and her ophthalmologic examination was normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: p.V84L (c.463G>T)

ClinVar: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: CA020170 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.250G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

At age 9, a male caucasian patient was admitted with hypertension and tachicardia. His history included café-au-lait spots since birth, four months of night sweats and three weeks of fevers, bifrontal headaches and fatigue. An MRI scan showed a 3cm left adrenal mass and an MIBG showed increased activity in the left adrenal gland. One month later the patient underwent a successfull adrenalectomy. Four years post-surgery, the patient presented with bitemporal headaches, fatigue and low-grade fevers but both MRI and MIGB are inconclusive. One year later, symptoms worsened, MRI results were negative. At 18Y he later relapsed with another adrenal pheochromocytoma which was resected. DNA analysis showed a germline mutation Val84Leu in VHL. This mutation could correspond to either c.250G>C or c.250G>T. Neither of the parents carried mutations of the VHL gene. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: None

KindredID: 1

Case: age, sex, ethnicity unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: A

Case: M, 11Y0M, Welsh

DiseaseAssertion: Pheochromocytoma

FamilyInfo: The patient had a sister that presented with bilateral pheochromocytoma at 17Y. The patient also had an asymptomatic parent.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L(c.250G>T)

LegacyVariant: p.V155L(c.463G>T)

CaseProblemVariantFreeText: bandshift in exon 1 and genomic sequencing indicated a G>T transversion at nucleotide 463, substituting a valine for leucine at codon 155 (V155L). Leading to NM_000551.3:p.V84L(c.250G>T)

ClinVarID: 2236, http://www.ncbi.nlm.nih.gov/clinvar/variation/2236

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L(c.250G>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive.

CohortInfo: Between September 1994 and December 1997, 16 unrelated individuals were referred to Genetic Services of Western Australia by local clinicians and by similar genetic services in other States, for VHL gene mutation analysis because of clinical manifestations suggestive of the diagnosis.

CasePresentingHPOs: HP:0002666, HP:0009711, HP:0010797 (pheochromocytoma, retinal capillary hemangioma, hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584, HP:0001737 (renal cell carcinoma, pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: p.V84L (c.463G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: VHL_2 (tumor ID)

KindredID: 2

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 25Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236, https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A