PatientID: 27

KindredID: 19

Case: M, 14Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: They had a 47Y family member (ID:26), however their relation is unclear.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient at 10Y was confirmed with VHL. He developed bilateral pheo at 10Y with recurrence 48M later.

CaseNotHPOs: HP:0002668; HP:0001737; HP:0010797; HP:0005584; HP:0030405; HP:0009711; HP:0000107 (paraganglioma, pancreatic cyst, hemangioblastoma, renal cell carcinoma, pancreatic endocrine tumor, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T124I (c.371C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 36902 https://www.ncbi.nlm.nih.gov/clinvar/variation/36902/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T124I (c.371C>T)

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 19

Case: M, 47Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: They had a 14Y family member (ID:27), however their relation is unclear.

CasePresentingHPOs: HP:0002666; HP:0030405; HP:0009711; HP:0000107 (pheochromocytoma, pancreatic endocrine tumor, retinal capillary hemangioma, renal cyst)

CaseHPOFreeText: The patient at 13Y was confirmed with VHL. He developed bilateral pheo at 13Y, which had recurrence at 48M later. He later at 47Y he developed a PNET. He also had renal cysts and retinal HB

CaseNotHPOs: HP:0002668; HP:0001737; HP:0010797; HP:0005584 (paraganglioma, pancreatic cyst, hemangioblastoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T124I (c.371C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 36902 https://www.ncbi.nlm.nih.gov/clinvar/variation/36902/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T124I (c.371C>T)

MultipleGeneVariants: N/A

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

PatientID: None (sister)

KindredID: 2

Case: F, Age unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Her sister and mother were found to carry the same mutation. Her mother was asymptomatic too (aged 48Y), while her sister (aged 25Y) was operated on for a carotid body tumour.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: An extensive clinical/physical examination was conducted: laboratory tests (urinary metanephrine and normetanephrine, plasma chromogranin A), an ophthalmoscopic examination and radiological exams (NMR of the brain, CT scan of the thorax and the abdomen) - all tests were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754382 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T152I (c.455C>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

PatientID: 7

KindredID: 7

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T124I (c.371C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36902, https://www.ncbi.nlm.nih.gov/clinvar/variation/36902/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transition

CivicName: T124I (c.371C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3682NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 3682NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma. Additionally, this family ID is stated again in Table 3 under the mutation c.163delG. Unclear if this is a typo, or if multiple mutations belong to this one family.

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: 7728151

SupplementalData: N/A

Variant: p.F76I (c.226T>A)

LegacyVariant: p.F76I (c.439T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 820994 https://www.ncbi.nlm.nih.gov/clinvar/variation/820994/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F76I (c.226T>A)

MultipleGeneVariants: N/A

PatientID: None (mother)

KindredID: 2

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Her 2 daughters were found to carry the same mutation. One daughter was asymptomatic too, while the other (aged 25Y) was operated on for a carotid body tumour.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: An extensive clinical/physical examination was conducted: laboratory tests (urinary metanephrine and normetanephrine, plasma chromogranin A), an ophthalmoscopic examination and radiological exams (NMR of the brain, CT scan of the thorax and the abdomen) - all tests were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754382 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T152I (c.455C>T)

MultipleGeneVariants: N/A

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

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

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: 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

PatientID: 24

KindredID: 24

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Negative family history.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: a carotid body (paraganglioma) was reported with no other details.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

CaseProblemVariantFreeText: Variant is written in paper under p.Tyr152Ile. This is incorrect however is paired to a paper where this variant it described (PMID: 18031321) referencing Thr152Ile, so this was deduced.

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:T152I (c.455C>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

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: N/A

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: paraganglioma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: Paraganglioma of the head and neck region (HNPGL): Left carotid body; nonsecreting paraganglioma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T152I (c.455C>T)

MultipleGeneVariants: N/A