PatientID: None

KindredID: 14

Case: Sex Unknown, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's father had a hemangioblastoma of the central nervous system at age 42. He was deceased before diagnosis could occur.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText: The patient presented with hemangioblastoma and renal cell carcinoma at age 29. At age 33, the patient presented with pancreatic cysts or tumours.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0009715 (retinal capillary hemangioma, pheochromocytoma, Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:29330336

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161*(c.481C>T)

MultipleGeneVariants: N/A

PatientID: II-4

KindredID: 3

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's mother (I-2) died as a result of pancreatic cancer. The eldest sister of the patient (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another sister (II-2) underwent surgery for breast cancer. The patient's two sons (III-6 and III-7) were found to harbour their father's VHL mutation. See Figure 3 for family pedigree.

CasePresentingHPOs: HP:0006770, HP:0001737, HP:0009713, HP:0000107, HP:0000787 (clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, renal cysts, nephrolithiasis)

CaseHPOFreeText: The patient was treated for kidney stones at age 33. At age 38 he was found to have a mass in the right kidney. Upper abdominal CT revealed the presence of multiple nodules and lumpy low-density areas in the left and right kidneys with uneven density. Multiple round low-density lesions were observed in the left and right kidneys, and in the pancreas. Brain CT revealed no abnormalities, but sphenoiditis was observed on the right side. Thoracic MRI revealed a round-shaped mixed signal (diameter, 12.0 mm) in the sixth thoracic vertebra. Contrast-enhanced scanning revealed minor enhancement, which appeared to indicate the presence of a hemangioma. Postoperative pathological analysis confirmed that the tumor was a clear cell renal cell carcinoma.

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

ClinVarID: 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: 5

KindredID: 3

Case: Sex Unknown, 49Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405; HP:0005584; HP:0010797; HP:0001737; HP:0009711 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, renal cell carcinoma, hemangioblastoma, pancreatic cyst, retinal capillary hemangioma)

CaseHPOFreeText: The patient developed PPGL at 33Y of age, and a PNET at 49Y. They were also recorded with all of the above manifestations

CaseNotHPOs: HP:0000107 (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: 2

KindredID: 2

Case: Sex Unknown, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had no family history of VHL disease. Although, patient’s daughter possesses the same mutation.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0002666 (retinal capillary hemangioma; renal cell carcinoma; abnormality of the pancreas; pheochromocytoma)

CaseHPOFreeText: The patient presented with retinal capillary hemangioma at age 12, as well as renal cell carcinoma, abnormality of the pancreas, and pheochromocytoma at age 33.

CaseNotHPOs: HP:0030424, HP:0030393, HP:0010797 (epididymal cyst, endolymphatic sac tumor, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: First cousin (male, 29Y, proband) presented with renal cell carcinoma, vitritis, retinal capillary hemangioma and retinal detachment. The proband also had the germline mutation found in his cousin.

CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0000648; HP:0000572 (Renal cell carcinoma, Hemangioblastoma, Retinal capillary hemangioma, Optic atrophy, Visual loss)

CaseHPOFreeText: He was operated on because of a CNS hemangioblastoma 3 years earlier. The patient stated that he had vision loss in his left eye after the CNS operation. About 2 weeks earlier, a partial right nephrectomy operation was performed due to RCC. The fundus examination revealed optic nerve atrophy and two RH (determined to be the cause of vision loss) at the equator in the left eye, and was normal in the right eye.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S68P (c.202T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621912, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA16621912

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S68P (c.202T>C)

MultipleGeneVariants: N/A

PatientID: 54

KindredID: 19

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 54) has a daughter who was genetically confirmed with the same mutation. The daughter was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband presented with a retinal angioma at 12, renal cell carcinoma and multiple pancreatic cysts/tumors at 33.

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

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: p.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692; https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: CIV:3

KindredID: C

Case: M, 33Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: A 4-generation family is given with 3 confirmed members with this mutation. 3 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0001737 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic cysts)

CaseHPOFreeText: diagnosed with right renal cell carcinoma, right adrenal pheochromocytoma and multiple pancreatic and renal cysts at the age of 33, but refused genetic screening.

CaseNotHPOs: HP:0010797; HP:0009711 (hemangioblastoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80I (c.239G>T) [assumed]

LegacyVariant: p.S80I (c.452G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 625229 https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

VariantEvidence: No genetic testing was done (patient refused), however family history and presentation leads to this assumption

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL2

Case: M, 33Y0M, 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: Table 1 of Supplementary

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had LOH found in the BAC array CGH data.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: None (proband 15)

KindredID: 15

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Father had died before diagnosis therefore no DNA sample available; He presented with CNS hemangioblastomas at the age of 42.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715; HP:0030393 (hemangioblastoma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis, endolymphatic sac tumor)

CaseHPOFreeText: Patient presented with hemangioblastoma at age 29, renal cell carcinoma at age 29, pancreatic cysts at age 36, endolymphatic sac tumor at age 33, papillary cystadenoma of the epididymis at age 29.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: AII2

KindredID: A

Case: F, 33Y0M, Serbian

DiseaseAssertion: VHL

FamilyInfo: Families were selected based on their clinical data and family history. Patient’s mother (AI1) had CNS hemangioblastoma. The patient’s son (AIII3) had severe arterial hypertension since 12Y0M and left pheochromocytoma was found and removed at 24Y0M. The patient’s sister (AII2) has pheochromocytoma and CNS hemangioblastoma. Genetic testing was performed on nine family members and two carried the heterozygous missense variant - current patient and her son. The patient’s mother and sister with VHL were not genetically tested. See pedigree in figure 1.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient was diagnosed with pheochromocytoma at 33Y0M.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93C (c.277G>T)

LegacyVariant: p.G93C (c.490G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 223175, https://www.ncbi.nlm.nih.gov/clinvar/variation/223175/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transversion

CivicName: G93C (c.277G>T)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Both of the patient’s brothers (Patient II-3 and II-4), the patient’s sister (II-5), and the patient’s nephew (III-3) were clinically diagnosed with VHL disease. Patient II-4 presented with RCCC at age 53, and carried the mutation NM_000551.3:c.269A>T. Patient III-3 presented with CH and carried the same mutation. The patient’s other brother (Patient II‐3) and sister (Patient II‐5) were deceased and had an undetermined mutation. Patient II-3 died of an advanced RCCC, and Patient II‐5 died of a ruptured CH. The patient’s parents (Patient I-1 and I-2) were also deceased from other causes. The patient’s grand-nephew (Patient IV‐1) was healthy and did not carry the mutation.

CasePresentingHPOs: HP:0006770; HP:0006880 (Renal clear cell carcinoma, cerebellar hemangioblastoma)

CaseHPOFreeText: The 45Y male patient was diagnosed with left RCCC at 33Y, but had no symptoms. The patient presented with complaints of headache and dizziness at age 41Y, and was diagnosed with a right cerebellar hemangioblastoma. In the most recent follow‐up, his symptoms had disappeared, and radiological imaging of the brain and abdomen revealed no recurrence.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient.

Variant: p.N90I (c.269A>T)

LegacyVariant: N/A

ClinVarID: 223172, https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I(c.269A>T)

MultipleGeneVariants: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient

PatientID: N/A

KindredID: 1

Case: M, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Genetic analysis of the patient's parents and brothers, who were unaffected, confirmed a diagnosis of de novo VHL disease.

CasePresentingHPOs: HP:0030424, HP:0009711, HP:0005584, HP:0006770, HP:0001737, HP:0000107 (epididymal cyst, retinal capillary hemangioma, renal cell carcinoma, clear cell renal cell carcinoma, pancreatic cysts, renal cyst)

CaseHPOFreeText: He was admitted to the hospital with a two-month history of progressive right flank pain, accompanied by a one-month history of recurrent painless gross hematuria. The patient's previous medical history included urological surgery at the age of 23 years due to an epididymal cyst and an ophthalmologic surgery at 26 years of age for retinal detachment resulting from bilateral retinal angiomatosis. Contrast-enhanced computed tomography (CT) scanning and angiography were used to detect the presence of quasi-circular enhancing lesions in the middle of the left kidney and large irregular enhancing lesions in the right kidney, extending into the vena cava, that formed an embolus. In addition, multiple cysts in the pancreas and kidney were detected radiologically. The patient underwent a radical nephrectomy with an embolectomy of the right kidney for treatment of T3b-stage renal cell carcinoma. After three months, he successfully underwent laparoscopic nephron-sparing surgery (NSS) of the left kidney. Histological analysis of the renal tissue revealed clear cell carcinomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S65W(c.194C>G)

MultipleGeneVariants: N/A

PatientID: II/1

KindredID: 1

Case: F, 33Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: A patient was found to have a mutation in the VHL gene (R161* (c.481C>T)), this patients parents were tested for the same mutation in VHL, but testing revealed no VHL gene mutation. Pedigree: see Figure 1.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: developed cerebellar hemangioblastoma at age 33

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

LegacyVariant: R161X (8684C>T)

ClinVar: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: IV-28 [written in Table 2 as IV-24 - typo]

KindredID: 1

Case: F, 33Y0M, Iranian

DiseaseAssertion: assumed VHL

FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation, one of which was this patient who proved to be symptomatic. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: HP:0011732; HP:0006880; HP:0010302 (abnormality of adrenal morphology, cerebellar hemangioblastoma, spinal cord tumor)

CaseHPOFreeText: Originally thought to be an asymptomatic carrier, however after follow-up was found to be symptomatic: brain MRI revealed multiple tutors, including a frontal mass (cerebellar tumor) with multiple spinal lesions, and an abdominal CT showed a 1.6x1.7 right adrenal mass. Additionally, this patient was pregnant at the time, to which was terminated at the 38th week of gestation with a caesarian section. She has two other children already.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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: IP (Proband)

KindredID: C

Case: M, 35Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Index patient presented with cerebellar hemangioblastoma, renal cysts, pancreatic cyst and bilateral renal cell carcinomas. Family members were not available for clinical and genetic screening except a brother whose screening revealed no abnormality.

CasePresentingHPOs: HP:0006880; HP:0005562; HP:0005584; HP:0001737 (Cerebellar hemangioblastoma, Multiple renal cysts, Renal cell carcinoma, Pancreatic cysts)

CaseHPOFreeText: Patient was operated for cerebellar hemangioblastoma at the age of 33 years. Preoperative clinical screening also showed renal cysts. Two years later, a pancreatic cyst and bilateral renal cell carcinomas were found and the patients underwent bilateral nephrectomy with subsequent chronic hemodialysis. Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Heterozygous deletion of Exon 3.

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 3 (Father)

KindredID: 10

Case: M, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 2 members of this family presented with the c.712C>T/c.499C>T germline variant of the VHL gene. ID 1 (Proband) was asymptomatic.

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (32Y), retinal angioma (33Y) and renal cell carcinoma (33Y).

CaseNotHPOs: HP:0000077; HP:0002666; HP:0001732 (Abnormality of the kidney, Pheochromocytoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: 11 (Father)

KindredID: 7

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family were found to harbor the c.319C>G germline variant of the VHL gene. ID 24 presented with renal abnormalities, and pheochromocytoma, and died at age 62. ID 1 presented with pheochromocytoma. ID 2 presented with pancreatic abnormalities. ID 10 presented with CNS hemangioblastoma, pancreatic abnormalities and pheochromocytoma. ID 4 presented with pheochromocytoma.

CasePresentingHPOs: HP:0002666; HP:0000077; HP:0001732 (Pheochromocytoma, Abnormality of the kidney, Abnormality of the pancreas)

CaseHPOFreeText: The patient presented with renal and pancreatic cyst or tumor (unspecified) (33Y), pheochromocytoma (21Y) and other undefined phenotypes (33Y).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.R107G (c.319C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43599, https://www.ncbi.nlm.nih.gov/clinvar/variation/43599/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: 217

KindredID: 81

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's brother had the same germline mutation, and presented with a CNS hemangioblastoma at 20, and a pheochromocytoma at 26. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732 (Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

Case: T030, M, 66

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 7 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.03, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.09

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.-2328T>G

c.2220G>A (p.Met740Ile)

c.3379 + 7A>C

c.3539-33G>A

c.3539-49C>T

c.4414dupC (p.His1472 fs)

c.5620 + 33-40delA

c.6554G>A (p.Arg2185Gln)

c.6902-5T>A

c.8418_8419insTCCC (p.Ser2807 fs)

Exon 28/52

Compound heterozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation

PatientID: B1

KindredID: 1

Case: Sex Unknown, 28Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: No testing

CasePresentingHPOs: HP:0009713, HP:0000107, HP:0001737 (spinal hemangioblastoma, renal cyst, pancreatic cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: no other clinical features were found after the cerebellar hemangioblastoma during 5 years 10 months of follow-up

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T124Mfs*33 (c.369_375del)

LegacyVariant: c.582_589delGACACAC

ClinVarID: N/A

CAID: CA913189240 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.369_375del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: T124Mfs*33(c.369_375del)

MultipleGeneVariants: N/A

令人震惊的数字：即便是全球最强的 AI Agent，在投行/咨询/律所的专业任务上也只有三分之一的成功率。更惊讶的是前三名几乎并列——GPT-5.4 的 33.3%、Claude Opus 4.6 的 33.0%、Gemini 3.1 Pro 的 32.0%——三家顶级实验室在专业服务 Agent 评测上的差距已缩小到统计噪声级别。「谁的 AI 更强」的问题，在这个维度上已经没有明确答案。

for - definition - numinous - primordial - Otto - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - definition - Gnosticism - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - in other words - going nto a sacred setting - is a counter force to alienation - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - definition - horror - alienation - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - adjacency - culture shock - example of domicide - when the agent-arena relationship is not in place - participatory knowing - meta-meaning system - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - definition - domicile - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - quote - to make significant, to reflect upon, to celebrate and enact Religio is to fundamentally enhance our agency, the disclosure of the world and our connectedness to it. And what else could be more valuable to us? What else could be more valuable to us? - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

quote - to make significant, to reflect upon, to celebrate and enact Religio is to fundamentally enhance our agency, the disclosure of the world and our connectedness to it. And what else could be more valuable to us? What else could be more valuable to us? - John Vervaeke - (see below) - And we do this, I would argue, - for the very good reason that - to make significant, - to reflect upon, - to celebrate and enact Religio - is to fundamentally - enhance our agency, - the disclosure of the world and our connectedness to it. - And what else could be more valuable to us? What else could be more valuable to us?

for - quote - subsidiary awareness - I cannot finalize it but can be aware of it - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke - definition - subsidiary awareness - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

quote - subsidiary awareness - I cannot finalize it but can be aware of it - John Vervaeke - (see below) - I’m always seeing by means of the I”. - It is phenomenologically mysterious to [us], but - it doesn't mean that I'm unaware of it. - I always have a subsidiary awareness. - I'm always aware through my “I” of my “me”. - I'm always aware through my framing of my framed. - I'm not completely out of touch with it. - It is not inaccessible to me, - but I cannot focalised it.

for - definition - relevance realisation transjectivity - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - quote - the machinery of relevance realisation is deeply phenomenologically mysterious to me - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - adjacency - framing process is outside of ANY frame we create -- eye cannot see itself - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - Relevance realization is pre-conceptual - it takes place at a level deeper than the level of beliefs - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke - to - YouTube conversation - Micheal Levin, John Vervaeke, Gregg Henrique - 2024 // ,- comment - In light of studying a John's concept of relevance realisation now, - after partially annotating the - Micheal Levin, - John Vervaeke, - Gregg Henrique - YouTube conversation, I should return to that annotation to - finish it and - take a more critical look for comparison between - Micheal Levin's goal oriented behaviour definition of life that drives and expanding cognitive light cone and - John Vervaeke's relevance realisation

to - YouTube conversation - Micheal Levin, John Vervaeke, Gregg Henrique - 2024 - https://hyp.is/go?url=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3DrAlmzRTbGDE&group=world

for - key insight / adjacency - relevance realization - I can never make a focal object of my framing, my capacity for relevance realization - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke - adjacency - focal object - framing - relevance realization - attention - intention - language - gestalt - infinite nesting - design - aspectualize - - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

adjacency - between - focal object - framing - relevance realization - attention - intention - language - gestalt - infinite nesting - design - aspectualize

adjacency - between - focal object - framing - relevance realization - attention - intention - language - gestalt - infinite nesting - design - aspectualize

adjacency - between - focal object - framing - relevance realization - attention - intention - language - gestalt - infinite nesting - design - aspectualize - adjacency relationship - As soon as we give attention to one aspect of our gestalt reality, we aspectualize, we frame - All of the below involve framing / aspectualizing - thinking - language use - design

for - example - what's it like to be dead? - phenomenologically impossible for me to perspectively know what it's like to be dead - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - definition - transframing - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - article - A Secular Wonder - Paolo Costa - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke - to - paper - A Secular Wonder - Paolo Costa - from book - The Joy of Secularism - 2011

to - paper - A Secular Wonder - Paolo Costa - from book - The Joy of Secularism - 2011 - https://hyp.is/Lj9-Ss7DEe-_3TvpOSe_Ew/www.academia.edu/433395/A_Secular_Wonder

for - quote / comparison - wonder and curiosity - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

quote / comparison - wonder and curiosity - Wonder isn't about problem solving - it is about remembering, by putting you deeply in touch with religio

for -comparison - wonder and curiosity - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

comparison - wonder and curiosity - curiosity drives you to focus and aspectualize one specific aspect of reality - wonder drives you to participate in the entire gestalt

for - definition - religio - John Vervaeke - means to bind together, to connect. Here it is used in the sense of binding that simultanously grounds the self and its world - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - quote - Relevance realization is pre-egoic - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

quote - Relevance realization is pre-egoic - John Vervaeke - (see below) - Relevance Realization is Pre-Egoic. - By the time you have ‘you’ in a ‘commonsensically’, obviated world of meaningful objects and situations, - Relevance Realization has already done a tremendous, tremendous amount of work.

for - relevance realization is pre-experiential - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

for - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke

question Relevance Realization - Depth? - How deep is it? - It's deeper than: - ego - your judgments of truth - goodness and beauty - your propositional thinking - your conceptualization - The way that can be spoken is not the way

for - paper - A Secular Wonder - Paolo Costa - 2011 - from book - The Joy of Secularism - from -

from - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke - https://hyp.is/FF8Nus6qEe-q25_Ha0_WGw/www.meaningcrisis.co/ep-33-awakening-from-the-meaning-crisis-the-spirituality-of-rr-wonder-awe-mystery-sacredness/

for - stats - climate change - emissions reductions from behavioral change - 33% reduction in EU

Find out more! What did the Treaty of Ghent say? In what ways did Russia mediate?

Cite your source(s)!

1:33:38 When there is new EVIDENCE, we CHANGE OUR MIND

https://typewriterdatabase.com/19xx-olivetti-eton.23086.typewriter

The Minimal Complete Typewriter Collection by [[Joe Van Cleave]]

Joe Van Cleave's personal six categories in a (his) typewriter collection: - Standard manual - medium-sized portable (largest segment in the collector's space) - lightweight portable or ultra-portable - typebar electric - IBM Selectric - Electronic typewriter (thermal typewriter), portable, quiet, battery operation.

Joe's minimal collection based on what he's got in his collection currently and the condition that they're in: - Royal KMM (his only standard) - Hermes 3000 (boxy middle era) - Olympia Splendid 33 (he's also got a Royal Mercury & Groma Kalibri) - Olympia Reporter - Selectric I (the only one he's got) cloth, ribbon cartridge system, no lift-off correction - Canon Typestar 220

Some of Joe's most important criteria in a typewriter: he prefers an elite face, 1 1/2 spacing, and bichrome setting.

At the time of this recording Joe had 30 typewriters.

AssayResult: 5.8

AssayResultAssertion: Normal

StandardErrorMean: 0.1

HGVS: NM_024675.3:c.26T>A p.(Leu9His)

AssayResult: 108.6

AssayResultAssertion: Not reported

PValue: > 0.9999

Comment: Exact values reported in Table S3.

HGVS: NM_024675.3:c.3428T>C p.(Leu1143Pro)

AssayResult: 24.31

AssayResultAssertion: Abnormal

ReplicateCount: 2

StandardErrorMean: 5.23

Comment: Exact values reported in “Source Data” file.

AssayResult: 30.27

AssayResultAssertion: Abnormal

ReplicateCount: 2

StandardDeviation: 1.04

StandardErrorMean: 0.74

Comment: Exact values reported in “Source Data” file.

HGVS: NM_024675.3:c.2840T>C p.(L947S)

AssayResult: 1.1

AssayResultAssertion: Abnormal

ReplicateCount: 27

StandardErrorMean: 0.8

Comment: This variant had loss of function of peak current (<10% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

HGVS: NM_198056.2:c.2783T>C p.(Leu928Pro)

AssayResult: 105

AssayResultAssertion: Normal

Comment: See Table S2 for details

AssayResult: 5

AssayResultAssertion: Abnormal

Comment: See Table S2 for details

HGVS: NM_000546.5:c.685T>C p.(Cys229Arg)

§§. 21-36 & § 91(1) of the Constitution Act, 1867

Referenced in Re: Authority of Parliament in relation to the Upper House, [1980] 1 SCR 54, 1979 CanLII 169 (SCC)

§§. 21-36 & § 91(1) of the Constitution Act, 1867

Referenced in Re: Authority of Parliament in relation to the Upper House, [1980] 1 SCR 54, 1979 CanLII 169 (SCC)

§§. 21-36 & § 91(1) of the Constitution Act, 1867

Referenced in Re: Authority of Parliament in relation to the Upper House, [1980] 1 SCR 54, 1979 CanLII 169 (SCC)

§.33 of the Constitution Act, 1867.

§§.24 and 33 of the Constitution Act, 1867.

On plantations slaves were often not allowed to practice religion or anything of their choice because they were not looked at a people. They had to find other ways to do this, so instead of having things like churches or massing they usually told stories that passed down from person to person