In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation was found in 2 family members with VHL disease (family ID 4402), using PCR and SSCP sequencing. The mutation of c.470C>T was referred to in the paper by c.683C>T due to a difference in transcript sequence. One carried pheochromocytoma and both carried retinal hemangioblastoma.

A cohort of 36 PCCs and four functional PGL tumours were analysed by exome-seq and high-density SNP-array analysis using tumor paired blood. This specified germline VHL mutation (tumor ID: VCB-PH-05T) belonged to a female diagnosed with recurrent phaeochromocytoma at age 12Y, surgery at 27Y. She also had a personal history of angioma of the right eye, laparotomy & numerous thyrocotomies, and a history of hypertension. The p.T157I (c.470C>T) mutation was also accompanied by a Germline SDHA mutation: c.113A>T (p.Asp38Val). Family history was unknown. Additionally, This patient was previously published in PMID: 26796762.

PatientID: 8

KindredID: 8

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, Retinal capillary hemangioma, Pheochromocytoma)

CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and pheochromocytoma.

CaseNotHPOs: HP:0001732; HP:0006770; HP:0000107 (Abnormality of the pancreas, Clear cell renal cell carcinoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: P1

KindredID: P1

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: Paraganglioma

FamilyInfo: N/A

CohortInfo: Tumour samples and paired peripheral blood samples were obtained from 39 patients, consisting of 31 PCs, seven extra adrenal PGLs and one metastasis from a malignant PC previously presenting with a PC.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: The patient had a malignant extraadrenal paraganglioma measuring 13 mm at age 27.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

GroupID: 22

Case: Sex unknown, Age unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: V240

KindredID: V240

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL Type 2A.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 683C>T) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.470C>T (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 45 had a p.Thr157Ile (c.470C>T) mutation. 2 members were affected: one had RCC and the other had RCC and pheochromocytoma. Other demographics of the members were not described.

PatientID: 1 (case)

KindredID: 1

Case: F, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Not significant - the paper states that the parents and siblings were negative for the mutation (indicating de novo).

CasePresentingHPOs: HP:0002666; HP:0009711; HP:0000479; HP:0012045 (pheochromocytoma, retinal capillary hemangioma, abnormal retinal morphology, retinal flecks)

CaseHPOFreeText: patient was referred for eye exam as part of a VHL screening program at 25Y. She has been diagnosed with bilateral pheochromocytoma at the age of 14 after an episode of acute hypertensive encephalopathy. Ophthalmoscopy disclosed in her right eye a small retinal hemangioma (1 disc diameter wide) along with feeder vessels in the mid-periphery and multiple, small, whitish, dome-shaped lesions scattered in the deeper layers of the posterior retina. Fluorescein and indocyanine green angiography confirmed the presence of the retinal hemangioma; multiple window-defects were also seen at the posterior pole and pericentral retina and hypofluorescent dots. (Unusual alterations of the deep retinal layers).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: p.T157I (c.683C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

The 25 year-old female patient was referred for eye exam as part of a VHL screening program. She had been diagnosed with bilateral pheochromocytoma at the age of 14 after an episode of acute hypertensive encephalopathy. Ophthalmoscopy disclosed in her right eye a small retinal hemangioma (1 disc diameter wide) along with feeder vessels in the mid-periphery and multiple, small, whitish, dome-shaped lesions scattered in the deeper layers of the posterior retina. Fluorescein and indocyanine green angiography confirmed the presence of the retinal hemangioma. Multiple window-defects were also seen at the posterior pole and pericentral retina and hypofluorescent dots. Electroretinogram and electro-oculogram findings were within the normal range of values. The visual field was normal with visual acuity of 20/20 in both eyes. DNA extracted with standard methods from peripheral blood leukocytes and quantitative Southern blot was performed to confirm the clinical diagnosis of VHL. PCR and SSCP were also performed to detect small mutations. A missense mutation at p.T157I (c.470C>T), reported in the paper as c.683 due to a difference in transciprt reference, was found in the patient. Both her parents and siblings were negative for the mutation, indicating a de novo mutation. 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.

GroupID: 45

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 2 individuals from a single family (ID 45).

GroupPresentingHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Renal cell carcinoma)

GroupHPOFreeText: Pheochromocytoma (1/2) and renal cell carcinoma (2/2).

GroupNotHPOs: HP:0009711; HP:0001732; HP:0010797 (Retinal capillary hemangioma, Abnormality of the pancreas, Hemangioblastoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: c.683C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

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. In addition, 35 positive controls were used to confirm this method. This patient was a positive control who has been previously sequenced (not referenced). One patient was found with the T157I (c.470C>T) VHL mutation. No family history was mentioned or clearly stated of their phenotypes.

PatientID: None

KindredID: 11

Case: age, sex, ethnicity unknown

DiseaseAssertion: Unknown

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Described as a positive control but not stated anything further

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely previously published - not clear where the controls came from/ how they were used.

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

Tumour samples and paired peripheral blood samples were obtained from 39 patients either with pheochromocytoma or paraganglioma. PCR and denaturing HPLC (dHPLC) was carried out for all coding exons of SDHB, SDHD, VHL and RET exons 11 and 13. Where a mutation was identified it was confirmed by direct sequencing. Patient P1 was a 27Y female at the time of surgery with a malignant extra adrenal paraganglioma an a germline mutation in the VHL gene (c.470C>T. p.Thr157Ile). Family history and other phenotypes were not described.

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The T157I (c.470C>T) germline missense mutation of the VHL gene was found in two VHL patients (23Y and 26Y). Both had retinal hemangioblastomas and pheochromocytoma (index cases 8 and 19). The 23 yr old patient also had hemangioblastomas of the central nervous system.

PatientID: N/A (case)

KindredID: 1

Case: F, 45Y0M, Italian

DiseaseAssertion: Assumed VHL

FamilyInfo: Genetic analysis was performed on the patients relatives, including her daughter. Her 55Y0M brother had the same mutation but no clinical signs of VHL disease.

CasePresentingHPOs: HP:0006748; HP:0030405 (adrenal pheochromocytoma, pancreatic neuroendocrine tumour)

CaseHPOFreeText: At 22Y0M, she had surgery for a right adrenal pheochromocytoma. Two years later, a pancreatic oduodenectomy was performed to remove a pancreatic neuroendocrine tumor. 21 years later, abdominal lymph node metastases of the pancreatic neuroendocrine that was removed 21 years prior had occurred. Three abdominal nodules that were found to be neuroendocrine tumours immunohistochemical characteristics were removed. The patient’s clinical history suggested a hereditary endocrine syndrome.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: V-PH-05T

KindredID: 3

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No familial cancers/syndromic illnesses

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

CaseHPOFreeText: diagnosed with recurrent phaeochromocytoma at age 12Y, surgery at 27Y. She also had a personal history of angioma of the right eye, laparotomy & numerous thyrocotomies, and a history of hypertension. Presence of elevated catecholamines, but no further details.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHA, SDHB, SDHC, TMEM127

PreviouslyPublished: 26796762

SupplementalData: Yes (see table S1 and S10)

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: Stated as ENSP00000256474.2:p.Thr157Ile

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: Germline, SDHA, c.113A>T (p.Asp38Val)

PatientID: 37

KindredID: 37

Case: F, 26Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family positive for VHL. Father presented with CNS hemangioblastoma, pheochromocytoma and further unspecified phenotypes; was diagnosed with VHL Type 2A. Younger sister presented with pheochromocytoma; was diagnosed with VHL Type 2C. Genetic information was not provided for father and sister.

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

CaseHPOFreeText: Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 2A.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 11

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: There was said to be, at the time, no affected relatives

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

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0006476; HP:0006880; HP:0009711; HP:0000618; HP:0010797 (adrenal pheochorocytoma, paraganglioma, abnormality of the pancreatic islet cells, cerebellar hemangioblastoma, retinal capillary hemangioblastoma, blindness, hemangioblastoma)

CaseHPOFreeText: At 8Y, (in 1978), she was operated for a right pheochromocytoma; at age 13 for a contralateral pheochromocytoma; at age 15, for a 4-cm mass at the neck was diagnosed by selective arteriography as a carotid paraganglioma. The patient was then operated twice for cerebellar hemangioblastoma at age 22, leading to the diagnosis of VHL disease. At age 27, the patient was operated again for a retrocaval pheochromocytoma and for islet cell tumors. The patient was also repeatedly treated for bilateral retinal hemangioblastomas leading to blindness at age 32. At age 36, again a pheochromocytoma was removed

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T157I (c.470C>T)

LegacyVariant: p.T157I

CaseProblemVariantFreeText: The publication only provides the p., the mutation was able to be deduced to p.T157I (c.470C>T)

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A