PatientID: 3

KindredID: 3

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Strong family history. His grandfather died of a brain tumor at the age of 45, his cousin brother was operated for a bilateral PCC and his paternal uncle was diagnosed with hemangioblastoma.

CasePresentingHPOs: HP:0006748, HP:0000107, HP:0001737, HP:0010797 (Adrenal pheochromocytoma, renal cyst, pancreatic cysts, hemangioblastoma)

CaseHPOFreeText: Subsequent CECT revealed a posterior fossa fourth ventricle tumor with hydrocephalus. He underwent a suboccupalcraniatectomy with CI laminectomy with biopsy of the tumor along with VP shunt and then was referred to SGPGIMS. He underwent DSA embolization in view of hypervascular tumor and in preparation of excision. He had a hemangioblastoma of the brainstem.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174 https://www.ncbi.nlm.nih.gov/clinvar/variation/223174/

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: 139 (Second cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with retinal angioma (16Y). Age of diagnosis of pheochromocytoma and renal cell carcinoma is unknown.

CaseNotHPOs: HP:0000077; HP:0001732; HP:0010797 (Abnormality of the kidney, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

Variant: p.R167W (c.499C>T)

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II:1

KindredID: 1

Case: M, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: the patient’s father was observed to be affected with CNS hemangioblastoma at 50Y

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0009715 (hemangioblastoma; retinal capillary hemangioma, Papillary cystadenoma of the epididymis)

CaseHPOFreeText: patient had hemangioblastomas diagnosed at 37Y, retinal capillary hemangioma at 31Y, and epididymal/ovarian cystadenoma at 16Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 2,3 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: 18

KindredID: A

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

CasePresentingHPOs: HP:0009711; HP:0002668 (Retinal capillary hemangioma, Paraganglioma)

CaseHPOFreeText: Retinal angiomas aged 16Y. 30Y at VHL diagnosis. Abdominal paraganglioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y185* (c.555C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223233, https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y185* (c.555C>G)

MultipleGeneVariants: N/A

PatientID: 242

KindredID: 93

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 242) has a mother (patient 243) who presented with renal cell carcinoma and multiple pancreatic cysts/tumors at age 43, but passed away before diagnosis/ before she could be confirmed with the mutation.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and retinal capillary hemangioma at age 18, and multiple pancreatic cysts/tumors at age 16.

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

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: Exon 1 Deletion (c.1-?_340+?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 1 Deletion

MultipleGeneVariants: N/A

PatientID: II

KindredID: 5

Case: Sex Unknown, 20Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 family members with the same VHL variant. Patient 5-I presented with retinal hemangioblastoma (17Y). Patient 5-III presented with retinal hemangioblastoma (12Y), pancreatic cysts (12Y), CNS hemangioblastoma (15Y) and kidney disease (12Y).

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0001737 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL at age 3Y. Presented with 13 CNS hemangioblastomas (11Y, 13Y, 15Y and 17Y), retinal hemangioblastoma (13Y) and 2 pancreatic cysts (16Y). Age at the end of study: 20Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145* (c.433C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625249, https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

CivicName: Q145* (c.433C>T)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 13

Case: Sex Unknown, 48Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797, HP:0001737, HP:0009711 (hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseHPOFreeText: The patient was diagnosed with VHL at age 13. The patient had 8 retinal hemangioblastomas at ages 13, 16,17,18. The patient had 1 pancreatic cyst at age 17 and one CNS hemangioblastoma at age 17. The patient died at age 48.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19863552, 25834951, 27966541, 27539272

SupplementalData: N/A

Variant: p.S65W(c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S65W(c.194C>G)

MultipleGeneVariants: N/A

PatientID: III

KindredID: 9

Case: Sex Unknown, 24Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: Two other family members (9-I and 9-II) carried the same mutation but were asymptotic.

CasePresentingHPOs: HP:0010797, HP:0001737 (hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: The patient had two CNS hemangioblastomas and two pancreatic cysts at age 16. The patient was diagnosed with VHL at age 16.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19863552, 25834951, 27966541, 27539272

SupplementalData: N/A

Variant: p.S65W(c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S65W(c.194C>G)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied at have the L198P mutation, however the asymptomatic father of patient C II-1 was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.593T>C (p.Leu198Pro)

PatientID: N/A (Case 3)

KindredID: 1

Case: Sex Unknown, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s two younger 9Y0M twin siblings possessed the same VHL variant and had abnormal vestibular assessments.

CasePresentingHPOs: HP:0001756 (Vestibular hypofunction)

CaseHPOFreeText: Following a genetic VHL diagnosis, patient presented with no audiovestibular symptoms. Vestibular assessment highlighted covert saccades in the left posterior semicircular canal on vHIT. Patient also showed signidicant assymmetry with weakness on the right side.

CaseNotHPOs: HP:0009713; HP:0006880 (spinal hemangioblastoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: peripheral hearing assessment and screening MRI of brain/spine were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1-3 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 17Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: N/A - no family history of VHL disease. Authors indicate probably a de novo mutation, however no testing on family members was completed.

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0100615 (pheochromocytoma, pancreatic endocrine tumor, ovarian neoplasm)

CaseHPOFreeText: hospitalized in 2011 (11Y old) due to a hypertensive crisis with end-organ damage (bilateral papilledema and left ventricular hypertrophy). MRI showed 2 heterogenous nodular lesions where the largest was in the right adrenal gland (65x51x39mm) and the other in the left adrenal gland (36x28x25mm). A bilateral adrenalectomy diagnosed both tumors as pheochromocytomas of the adrenal gland. Lymph node metastasis was detected in the adipose tissue surrounding the left adrenal gland. 2 years later (at age 13Y) a PET/CT scan showed a nodular lesion in the tail of the pancreas (11mm) and a nodule in between the inferior vena cava and the portal vein (13mm) and both were later diagnosed as neuroendocrine tumors the former in the pancreas and the latter in the perihaptic ectopic pancreatic tissue. At 14Y, more pancreatic lesions were found. At 16Y, an MRI found a nodule int he right ovary (33mm) which was later diagnosed as a benign ovarian steroid cell tumor

CaseNotHPOs: HP:0010797; HP:0006770 (hemangioblastoma, clear cell renal cell carcinoma)

CaseNotHPOFreeText: Table 1 indicates this was did not have the above manifestations

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 1

Case: M, 57Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0000107; HP:0006748; HP:0009713; HP:0009711; HP:0006880; HP:0030405; HP:0001737 (renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, retinal hemangioblastoma, cerebellar hemangioblastoma, pancreatic endocrine tumor, pancreatic cysts)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 16Y0M. He was found to have renal and pancreatic cysts, adrenal pheochromocytoma, spinal hemangioblastoma, retinal hemangioblastoma, cerebellar hemangioblastoma, and pancreatic endocrine tumor (see table 1). Patient also had bone metastasis. He was diagnosed with VHL subtype 2A at age 49Y0M and passed away at age 57Y0M.

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 13

KindredID: 6

Case: M, 22Y11M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 6, patient 12 was reported as having PPGL and PNETs at 36Y, along with renal and pancreatic cysts, and retinal HB. Their relation is not clear.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient developed PPGL at 16Y of age. It was a right side Pheo measuring 1.7cm with no recurrence at follow up 83 Months after.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III:6

KindredID: 1

Case: M, 18Y, Spanish

DiseaseAssertion: VHL

FamilyInfo: Spanish family of 15 members studied, over 2 generations. 6 members had VHL presentations, 1 was a carrier, and 4 others had the mutation, while 2 were not sequenced. This patient’s sister had passed at 18Y with pheochromocytoma, his other sister presented with the same mutation. His father, aunt and two cousins all showed positive for the familial mutation.

CasePresentingHPOs: HP:0006748; HP:0009711; HP:0006880 (adrenal pheochromocytoma; retinal capillary hemangioma, cerebellar hemangioblastoma)

CaseHPOFreeText: at 16Y, he presented and had removed with bilateral adrenal pheochromocytoma (right: 2.7cm; left 4.7cm) with signs and symptoms of intracranial hypertension. At 17Y, brain CT and MRI were abnormal, showing cerebellar tumors (hemangioblastoma). Retinal angiomas were also displayed in this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

LegacyVariant: p.R238T, C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III-2

KindredID: 1

Case: M, 16Y0M, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo:  2 young male twins were examined with the VHL gene mutation with simultaneously manifesting hemangioblastomas of the right cerebellar hemisphere. Both parents were examined with no VHL mutation, detecting a de novo mutation in the twins. A third sibling, two years older, presented with a cafè au lait skin spot. Grand mother had bilateral high myopia and glaucoma. The medical history of the pedigree shows that member (I-1) had severe hypertension and died at 60 from a stroke, member (I-2) died at 40 from ovarian carcinoma, and member (I-3) died at 54 from clinically diagnosed intracerebral haemorrhage.

CasePresentingHPOs: HP:0006880; HP:0009713 (cerebellar hemangioblastoma, spinal hemangioblastoma)

CaseHPOFreeText: in 1994 patient came complaining of blurred vision thought to be due to his myopia. MRI showed a large cyst and a 4.3 cm mural ovoid nodule in the right cerebellar hemisphere. Another small mural nodule was present in the infero-posterolateral portion of the right cerebellar hemisphere. CT disclosed a round homogeneous, hyperintense nodule at T1 in the spinal cord. Raised intracranial pressure due to the compression of aqueduct from the tumour accounted for hydrocephalus and enlarged lateral and 3rd ventricles.

CaseNotHPOs: HP:0001901 (polycythemia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 1

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother was found with the same VHL germline variant. His mother presented with bilateral pheochromocytoma.

CasePresentingHPOs: HP:0002315; HP:0000651; HP:0002666; HP:0009711; HP:0000822 (Headache, Diplopia, Pheochromocytoma, Retinal capillary hemangioma, Hypertension)

CaseHPOFreeText: Admitted with complaints of headache and diplopia. MRI indicated the presence of multiple lesions in perivascular areas neighboring both adrenal glands. An iodine 123 metaiodobenzylguanidine (MIBG) scan revealed multiple focal areas of increased uptake near the adrenal glands. The diagnosis of bilateral pheochromocytoma was confirmed histologically and immunohistochemically. The patient remained asymptomatic with no laboratory or radiologic abnormalities for six years of follow-up. At the age of 16, the patient was referred to our clinic with a visual defect in the left eye. Ophthalmologic examination led to the diagnosis of bilateral retinal hemangiomas, and he underwent laser photocoagulation.

CaseNotHPOs: HP:0009713; HP:0006880 (Spinal hemangioblastoma, Cerebellar hemangioblastoma)

CaseNotHPOFreeText: Cerebral, spinal MRI and abdominal computed tomography (CT) were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: c.695G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant was reported as “c.695G>A” which was mapped to p.Arg161Gln (c.482G>A) in accordance with reference sequence NM_000551.3.

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: II-a

KindredID: 1

Case: F, 16Y0M, Greek

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s 50-year-old father has VHL consisting of retinal HBs diagnosed at the age of 20 years. He also has spinal cord HBs located in the neck. He was also found to carry the mutation NM_000551.3:c.433C>T that the patient carried. The patient’s 18-year-old brother and her 20-year-old sister are phenotypically healthy and repeated biochemical evaluation and imaging studies are negative. Her paternal uncle, aunt and cousins are also phenotypically healthy with no indications from either biochemical or imaging studies as they denied further evaluation. In addition, her paternal grandfather of unknown genotype died at the age of 85 years while her paternal grandmother is alive and has no problems, being 86 years old at time of writing.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0001737 (Spinal hemangioblastoma, cerebellar hemangioblastoma, retinal hemangioblastoma, pancreatic cyst)

CaseHPOFreeText: The 16Y female patient first presented with back pain, headaches, numbness, dizziness, weakness and pain in the arms and the legs at 12Y. A hemangioblastoma in the thoracic spine and a hemangioblastoma in the neck were found. A year later, at the age of 13, multiple HBs in the right and smaller lesions in the left eye were found. Two asymptomatic cysts (2 cm and 0.8 cm) in the body of the pancreas were also found. During her recent evaluation, at the age of 16 years, MRI imaging revealed a large HB extending from the cerebellum to the Th8 vertebrae, with extensive solid and cystic nodules inside the mass and increased dimensions of the spinal cord.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145*(c.433C>T)

LegacyVariant: N/A

ClinVarID: 625249, https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

gnomAD: N/A

VariantEvidence: It has been documented that dynamic organisation of pVHL–HIF1α recognition is focally centred on Gln145 within the L7 loop, and its tumourigenic mutant Q145H abolishes almost all of the correlated dynamic motions. In this report, Q145 is substituted by a stop codon, p.Q145X. This is a nonsense mutation resulting to a truncated VHL protein that lacks the last 68 amino acids and thus its function is abolished.

MutationType: stop_gained

CivicName: Q145*(c.433C>T)

MultipleGeneVariants: N/A

PatientID: II.6

KindredID: F8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Presented with retinal capillary hemangioma. Tumor detected at age 16.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+648T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827583, https://www.ncbi.nlm.nih.gov/clinvar/variation/827583/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transition; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+617C>G

PatientID: 4

KindredID: 4

Case: 16Y1M, sex unknown ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0009713; HP:0001737; HP:0000107 (cerebellar hemangioblastoma; retinal capillary hemangioma; spinal hemangioblastoma; pancreatic cysts; renal cyst)

CaseHPOFreeText: spinal hemangioma was cervical.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.341-1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 823743 https://www.ncbi.nlm.nih.gov/clinvar/variation/823743/

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline G to A base change at 1 position of splice acceptor sequence for exon 2

MutationType: splice_site_variant

CivicName: Splice Site (c.341-1G>A)

MultipleGeneVariants: N/A

PatientID: 277

KindredID: 108

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 277, presented with a CNS hemangioblastoma at age 16, retinal angioma a 20, and renal cell carcinoma at 28. Their father who passed away before diagnosis presented with a CNS hemangioblastoma at 48.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseHPOFreeText: The proband, patient 277, presented with a CNS hemangioblastoma at age 16, retinal angioma a 20, and renal cell carcinoma at 28.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas)

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: 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: 280

KindredID: 110

Case: M, 22Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22. Their father presented with a CNS hemangioblastoma at age 25, and retinal angioma at age 29.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732; HP:0009711 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseHPOFreeText: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22.

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

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: 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: 1

KindredID: 1

Case: M, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Eight patients whose pheochromocytomas were suggestive of VHL but were negative for a VHL abnormality both by PCR-Sanger sequencing and by quantitative multiplex PCR of short fluorescent fragments (QMPSF).

CasePresentingHPOs: HP:0010797, HP:0002666, HP:0030405, HP:0006748 (Hemangioblastoma, Pheochromocytoma, Pancreatic endocrine tumor, adrenal pheochromocytoma)

CaseHPOFreeText: Patient developed hemangioblastoma at age 16. At age 17 he developed right pheochromocytoma, pancreatic endocrine tumour, and a small left adrenal nodule later stated to be an adrenal pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient is believed to be the same as a patient published in 30731206. That paper offers more updated information on this patient.

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 5.7%.

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: 42

KindredID: 5069

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 41) has the same VHL mutation and presents with five pathologic pancreatic endocrine tumours.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with three pathologic pancreatic endocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: p.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 50

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Third child of healthy unrelated parents; she has two healthy older sisters.

CasePresentingHPOs: HP:0001511; HP:0001999; HP:0000952; HP:0001943; HP:0001508; HP:0000851; HP:0001250; HP:0002650; HP:0001332; HP:0001263; HP:0006880 (Intrauterine growth retardation, Abnormal facial shape, Jaundice, Hypoglycemia, Failure to thrive, Congenital hypothyroidism, Seizure, Scoliosis, Dystonia, Global developmental delay, Cerebellar hemangioblastoma)

CaseHPOFreeText: Normally born after 37 weeks pregnancy. During the prenatal period, she showed intrauterine growth retardation of unknown cause. At birth, dysmorphic features were noted (full list in table 1). After birth, she was treated for physiological jaundice and hypoglycemia. In addition, she has problem for failure to thrive and feeding difficulties associated with poor sucking and regurgitation. Furthermore, she was diagnosed with a congenital hypothyroidism in the neonatal screening. At 26 months old, she developed epilepsy. At 7Y, was considered to have Rett syndrome because of stereotypic hand movements since 2 years old, scoliosis and dystonia. Her psychomotor development was severely delayed: she had no ability to move by herself, visual contact, or social interaction. Brain MRI was performed at 1 year old and 6 years old. Both of these showed no abnormal findings. At 16 years old, follow-up MRI unexpectedly demonstrated a solid tumor with peritumoral edema at right cerebellum; diagnosed a cerebellar hemangioblastoma and confirmed through histopathology.

CaseNotHPOs: HP:0002012 (Abnormality of the abdominal organs)

CaseNotHPOFreeText: Repeat brain MRI, fundoscopy, abdominal echography and CT, blood and urine testing revealed no other tumors associated with VHL.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: No mutation was detected in MECP2 on chromosome Xq28. At 5 months old, her chromosome analysis of the white blood cells revealed a distal deletion of the short arm of chromosome 3. Genomic DNA from the patient and her parents revealed a de novo 11.0-Mb deletion at 3p26.3-25.3 that included VHL and a paternally inherited 740-kb gain at Xp22.2-22.13, which was predicted to be a benign copy number variation. Unfortunately, since the mutation analysis of VHL was not performed using resected tumor tissues in the present case, “the second hit” could not be confirmed. Thus, the reason remains unclear why a cerebellar hemangioblastoma developed in her.

MutationType: deletion

CivicName: 3p26.3-25.3 11Mb del

MultipleGeneVariants: see VariantEvidence.

PatientID: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied. This mutation was said to be a de novo, although no more inforation provided. However the asymptomatic father of patient was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198P (c.593T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223235 https://www.ncbi.nlm.nih.gov/clinvar/variation/223235/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: Proband 5

KindredID: 1

Case: M, 16Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral PCC diagnosed at 16Y and did not have any other clinical presentations. Stated as having VHL type IIC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

MultipleGeneVariants: N/A

PatientID: II.6

KindredID: F8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Presented with retinal capillary hemangioma. Tumor detected at age 16.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+617C>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827582, https://www.ncbi.nlm.nih.gov/clinvar/variation/827582/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+648T>C

PatientID: I

KindredID: 18

Case: Sex Unknown, 48Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0000112 (Pancreatic cysts, Nephropathy)

CaseHPOFreeText: Diagnosed with VHL at age 14Y. Presented with 3 pancreatic cysts (14Y) and kidney disease (16Y). Age at the end of study: 48Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q203Tfs*53 (c.606dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 935385, https://www.ncbi.nlm.nih.gov/clinvar/variation/935385/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: Q203TfsX53 (c.606dupA)

MultipleGeneVariants: N/A

PatientID: III

KindredID: 17

Case: Sex Unknown, 26Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 other family members were found to have this VHL variant. Patient 17-I was asymptomatic. Patient 17-II presented with CNS hemangioblastoma (8Y).

CasePresentingHPOs: HP:0009711; HP:0001737 (Retinal capillary hemangioma, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with 6 pancreatic cysts (15Y) and retinal hemangioblastoma (16Y). Age at the end of study: 26Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1 Deletion (c.1-?_340+?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 1 Deletion

MultipleGeneVariants: N/A

PatientID: I

KindredID: 7

Case: Sex Unknown, 40Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: One other family member presented with this variant and was asymptomatic.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 4Y. presented with 3 retinal hemangioblastomas (8Y, 16Y). Age at the end of study: 40Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II:3

KindredID: 2

Case: F, 16Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: the patients father was found with the same exon deletion and hemangioblastomas at 28Y, retinal angiomas and RCC at 41Y, and multiple pancreatic cysts or tumors as well as pheochromocytomas at 42Y. Her two other siblings were not observed or tested.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: patient was found with hemangioblastomas at 16Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 1 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: exon 1 deletion

MultipleGeneVariants: N/A

PatientID: DIII7

KindredID: D

Case: F, 16Y0M, Chinese

DiseaseAssertion: pancreatic cysts

FamilyInfo: A 3-generation family is given with 3 confirmed members with this mutation. 2 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0001737 (pancreatic cysts)

CaseHPOFreeText: initially diagnosed by genetic analysis and further verified radiologically, to be found with pancreatic cysts at 16Y.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584 (hemangioblastoma, pheochromocytoma, retinal capillary hemangioma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

LegacyVariant: p.F76del (c.439delTCT)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_2289delTCT)

MultipleGeneVariants: N/A

PatientID: 83 (Cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (25Y), retinal angioma (16Y) and pancreatic tumors or cysts (undefined) (22Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

Variant: p.R167W (c.499C>T)

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5 (Aunt)

KindredID: 17

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family tested positive for the c.496_506del germline variant of the VHL gene. ID 4 presented with CNS hemangioblastoma, retinal angioma and renal and pancreatic abnormalities. ID 1, 25 and 8 were asymptomatic.ID 22 presented with CNS hemangioblastoma. 2 members were assumed to have the variant but were not genetically confirmed (ID 20 and ID 11). ID 11 and 20 presented with CNS hemangioblastoma.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: This patient presented with retinal angioma (16Y).

CaseNotHPOs: HP:0005584; HP:0002666; HP:0010797; HP:0000077; HP:0001732 (Renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Abnormality of the kidney, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.V166Sfs*4 (c.496_506del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223229, https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

CAID: N/A

gnomAD: N/A

VariantEvidence: It is unclear from the publication if this variant is reported according to legacy (AF010238.1) or NM_000551.3 reference sequence. Clinical notes from the case confirm the reference sequence to be NM_000551.3.

MutationType: deletion; minus_2_frameshift_variant

CivicName: V166SFS*4 (c.496_506del)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: F, 28Y0M, German

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748, HP:0006880, HP:0009713, HP:0030405, HP:0010302 (Adrenal pheochromocytoma, cerebellar hemangioblastoma, spinal hemangioblastoma, pancreatic endocrine tumour, spinal cord tumor)

CaseHPOFreeText: At age 16 she presented with a left adrenal pheochromocytoma which was removed laparoscopically. At age 28, a cystic cerebellar hemangioblastoma was removed. In 2010, she was admitted to the Freiburg Preventive Medicine Center. Baseline MRI detected multiple intraspinal hemangioblastomas associated with tumor cysts. Abdominal MRI also showed a 5.6 × 5.4 cm solid tumor in the pancreatic tail that was richly vascularized. Three of eleven lymph nodes showed metastases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 29Y0M, Brazilian

DiseaseAssertion: VHL

FamilyInfo: VHL type 1. Genetic testing has been performed in her parents and brother with negative results. Her only child has not undergone predictive testing yet.

CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0000107; HP:0001737; HP:0001407 (endolymphatic sac tumor; retinal capillary hemangioma; hemangioblastoma; renal cysts; pancreatic cysts; hepatic cysts)

CaseHPOFreeText: endolymphatic sac tumor diagnosed at 11Y, retinal angiomas at 16Y; hemangioblastoma, renal, pancreatic, and hepatic cysts at 29Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.Q73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: III-5

KindredID: Family A

Case: F, 32Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s grandfather (I-1), now deceased, and aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. Her mom II-2 had confirmed VHL and CNS hemangioblastoma; and her cousin (III-6) has renal cell carcinoma and CNS/spinal hemangioblastoma and also the confirmed VHL gene mutation. Her uncle (II-3) has confirmed VHL gene and pancreatic and renal cysts. Her brother and sister (III-3; III-4) both were found with the confirmed VHL gene mutation; III-3 with retinal hemangioblastoma and CNS/spinal hemangioblastomas and III-4 with pancreatic and ovarian cysts. IV-1 and IV-3, were confirmed with the VHL gene mutation although no other manifestations.

CasePresentingHPOs: HP:0010797; HP:0009711 (CNS hemangioblastoma, retinal capillary hemangioblastoma)

CaseHPOFreeText: developed hemangioblastoma at the optic nerve in her left eye at the age of 16. At the age of 30, patient A III-5 underwent surgery for a CNS hemangioblastoma.

CaseNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 3 (c.464-?_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 3 Deletion

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 1

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 16Y0M. She had adrenal pheochromocytoma and diagnosed with VHL subtype 2A (see table 1).

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

GroupID: 42

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 of the 573 patients discussed in this paper were found to have identical variants. This mutation was found in 1 VHL family with 3 patients.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma, cerebellar hemangioblastoma, pheochromocytoma)

GroupHPOFreeText: 2 had retinal hemangioblastoma at a mean age of 16Y, one had cerebellar hemangioblastoma at 16Y, and 1 had pheochromcytoma at 14Y.

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

https://www.reddit.com/r/typewriters/comments/1v51cdy/help_identify_an_antique/

In Kolumbien wird der neugewählte rechte Präsident einen Rollback in der Umweltpolitik und bei der Energiewende einleiten. Er wird dabei auf gut organisierten Widerstand lokaler Communities und der Linken stoßen. Trotz der Politik der Regierung Gustavo Petro ist Kolumbien noch immer von Rohstoffexporten abhängig. Interessierte Machtgruppen setzen vor allem auf die Expansion des Kupfer-Bergbaus.

https://typecast.munk.org/2023/02/18/1967-womda-typewriter-typefaces-smith-corona-scm-fonts/

An example of the Elite Gothic No. 16 can be found on Reddit which has a "cross" foundry mark with 1, 6, S, empty in the four quadrants from top to bottom and left to right.

Connie’s mother uses June to compare with Connie, I think her mother wants to take Connie’s pride and her beauty.

Tom’s presence disrupts the carefree atmosphere of Gatsby’s parties and bring tension.

Gatsby learns early on how charm and ambition can help him reshape his identity and move closer to his dreams.

yess even gastby sees daisy inside , i don;t get it why tom ignore her

even nick sees his emotion,he saw the interaction between daisy and gastby

yess they are finally interacting,i can tell gastby pretend to be calm

Gatsby rejects his real background and creates a new identity based on an idealized version of himself rather than reality.

It is surprising how Tom, who usually dominates every situation, appears genuinely afraid of losing control. His repeated glances back at Gatsby’s car reveal an unexpected vulnerability, as if Daisy might suddenly escape his life altogether.

This sentence reveals how unstable Gatsby’s self-narrative has become. His words no longer sound deliberate but defensive and automatic. It suggests that the persona he performs is slipping beyond his control.

This line shows Daisy’s tendency to turn emotion into decorative fantasy. Her affection is expressed through imagery rather than commitment. It suggests that her love remains playful and unreal, even in an intimate moment.

I can’t imagine how stress Connie would be if she’d to heard those kind of salty remarks that keep compare her with her sister.

Her mother used the word “gawking”, I think it’s kind of impolite to her daughter. Her mother seemed to be irritated to her that she had to used such an indecent word.

It’s interesting here because it’s impossible in real life that one can know everything about the other. But the author made Connie’s mother be a person who omniscient about her daughter.

It is surprising that a teenage girl would wish for both her mother and herself to die just because of family arguments.

It shows that Connie’s entire sense of identity is based on her appearance.

It’s troubling because she never said her name but he knew it.

The way the author uses "toldja" is weird, is the author emphasize Anrold's friend talking voice.

I am surprised that Connie is so brave and confident to refuse Anrold's friend

This sentenceis interesting because the author writes out the scene which Connie is free and happy with her friends.

This passage is interesting because Arnold Friend seems both clumsy and in control. His strange movements make him look unpredictable and threatening, which makes me feel tense.

This is troubling because Arnold’s words sound friendly at first, but they actually suggest danger and coercion. It shows that Connie is being lured into a situation she can’t control, creating fear and suspense.

It is surprising that, at only fifteen, she already believes beauty is the most important thing in life.

We done really know who made the bump but the language, I think, suggests a deeply rooted Misogyny.

I'm surprised that Connie and I have the same feeling because of Mom's constant nagging.

Initially, Connie clearly expresses that her mom doesn't like her, but in this paragraph, she says her mom prefers her to June, and sometimes they act like friends. However, they seem to pretend to argue. That is interesting to me.

In the beginning, I think the boy only knows Connie's name, but in this paragraph, he tells her that he knows where her family goes, how long they will be gone, and even the name of her best friend. It makes me feel uncomfortable.

That part where Arnold pretends Connie already agreed to go with him is troubling because it feels manipulative and fake.

I didn't find that Arnold's friend was even older than him.

This paragraph vividly portrays Arnold’s image and makes readers sense that something is off about him.

The way he introduced his name was strange, and he even marked numbers on his car, which makes people question his identity and purpose.

This is interesting because it reminds me that teenage girls often pay close attention to their appearance.

This really surprised me,why would someone use such a flirtatious tone when meeting a person for the first time??

The stutter gave it away that he's attempting to fabricate a lie. Or that he really had seen them before. It's vaguely put. Either way, it's extremely alarming.

Her mother, to add salt to the wound, would praise her sister, June. Whatever June is Connie isn’t. A distraught favoritism at play.

In two words, it shows the eventual submission, a quiet sacrifice. Extremely powerful.

The sharp contrast between his skin suggests he had been chronically predatory.

It's interesting to see how she downplays her friendship with Pettinger, an attempt to have it fly under her mother's radar, preserving her social life.

An uncertain fate awaits Connie as she is taken away. Whether she really recognize the place or not, the landscape here represents uncertainty, vast and unknown.

I think this sentence was very interesting is because it shows that Connie is two different people at home and outside. It feels like the common phenomenon among teenagers: "one way in front of parents, another way outside."

Human beings eager to acknowledge how the world works and who we are .

Lanier, J. (2013). Who Owns the Future? Simon & Schuster. https://amzn.to/3YzotPZ

Annotations <br /> alternate link for annotations

Things I Never Knew about my Father by Lisa Jardine<br /> https://soundcloud.com/conwayhall/things-i-never-knew-about-my

See also: https://web.archive.org/web/20141216103656/http://www.conwayhall.org.uk/lisa-jardine

https://en.wikipedia.org/wiki/David_Reich_(geneticist)

Going Dutch: How England Plundered Holland's Glory <br /> by Lisa Jardine

Gramsci′s Common Sense<br /> by [[Kate Crehan]]

https://en.wikipedia.org/wiki/Gilbert_White

THE SEX DIARIES OF JOHN MAYNARD KEYNES<br /> by [[Evan Zimroth]] in More Intelligent Life accessed on 2025-08-15T12:20:39

https://www.facebook.com/groups/705152958470148/posts/1041040904881350/

https://www.carbonbrief.org/explainer-how-china-is-managing-the-rising-energy-demand-from-data-centres/?utm_source=cbnewsletter&utm_medium=email&utm_term=2025-04-16&utm_campaign=Daily+Briefing+16+04+2025

https://www.liberation.fr/environnement/incendies-a-los-angeles-nous-assistons-a-un-basculement-important-dans-la-saisonnalite-des-feux-20250115_2RPAYNV4HRDW7MAMEZQJBZT2YM/

for - book - Sacred civics - ch 16 - Commons Economies in Action - Mutualizing Urban Provisioning Systems - Michel Bauwens - Jose Ramos - Ron Kranjc

Die Vollinvasion der Ukraine hat bereits nach wenigen Wochen zu Rekordgewinnen für die großen Ölgesellschaften geführt. Vor allem die saudische Firma Aramco investiert die Einnahmen in weitere fossile Expansion. https://www.newstatesman.com/spotlight/sustainability/climate/2022/05/saudi-arabia-is-the-biggest-beneficiary-of-the-war-in-ukraine