PatientID: 23

KindredID: 2

Case: F, 18Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: No family history, assumed de-novo, but unclear if parents were tested to confirm de-novo assertion.

CohortInfo: 36 pediatric patients with pheochromocytomas and/or parangangliomas.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient was found to have a benign norepinephrine secreting pheochromocytoma at age 18.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/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: N/A

KindredID: 3

Case: Sex Unknown, 18Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: This patient (a relative of patient B3) had two first degree relatives who were positive for the VHL mutation. The first family member (patient B3) had a cerebellar hemangioblastoma at 40 and a pheochromocytoma at 41 years old and the second family member had a renal cyst at 17 years old.

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

CaseHPOFreeText: N/A

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)

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: proband (F2-II-11)

KindredID: 2

Case: F, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patients son (F2-III-9) was a 9-year old male patient with a right adrenal pheochromocytoma. The son later presented with a left adrenal pheochromocytoma at 17-years-old. The patients niece (F2-III-4) was a 33 year old female with bilateral pheochromocytoma. The patients brother (F2-II-3) succumbed to hypertensive intracerebral hemorrhage 21 years prior to this study.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: presented with paroxysmal hypertension (180–210/100–120 mmHg), headache, palpitations and hyperhidrosis in 1985 at the age of 18. US scans showed an isolated mass in the right adrenal gland.

CaseNotHPOs: HP:0005584, HP:0000107, HP:0010797 (renal cell carcinoma, renal cyst, hemangioblastoma)

CaseNotHPOFreeText: no other systematic tumors, including CNS hemangioblastomas, renal cysts or renal cell carcinoma, were identified

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: CA020413

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: 18Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: isolated bilateral pheochromocytoma first presenting at 18Y

CaseNotHPOs: HP:0009715; HP:0005584; HP:0010797 (Papillary cystadenoma of the epididymis, renal cell carcinoma, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/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: 57

KindredID: 20

Case: F, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had a CNS hemangioblastoma at age 18. Their father (listed in this paper as the proband) presented with a retinal angioma at 32, a CNS hemangioblastoma at 34, and renal cell carcinoma as well as multiple pancreatic cysts/tumors at 38. Their father passed away before genetic testing could be confirmed.

CasePresentingHPOs: HP:0010797 (CNS Hemangioblastoma)

CaseHPOFreeText: The proband had a CNS hemangioblastoma at age 18.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma, 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: p.P86L (c.257C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L (c.257C>T)

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: 121

KindredID: 42

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 42) had four family members confirmed with the mutation: his son (CNS hemangioblastoma at 12, retinal angioma at 11); his sister 1 (patient 116) presented with multiple pancreatic cysts/tumors at 53; his niece (daughter of sister 2) was asymptomatic at the time of assessment, and his nephew (son of brother 2) presented with a CNS hemangioblastoma at 12, and pheochromocytoma and multiple pancreatic cysts/tumors at 18. The proband also had three family members who passed away before diagnosis/ before they could be confirmed with the mutation: his sister 2 (patient 117) had multiple pancreatic cysts/tumors at 46, his brother 1 presented with a CNS hemangioblastoma at 47, renal cell carcinoma at 59, and multiple pancreatic cysts/tumors at 59; and his brother 2 presented with a retinal capillary hemangioma at 43, and CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 44.

CasePresentingHPOs: HP:0010797, HP:0001737; HP:0001732; HP:0002666 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma)

CaseHPOFreeText: The proband's nephew (son of brother 2) had a CNS hemangioblastoma at 12, multiple pancreatic cysts and tumors at 18 and pheochromocytoma at 18.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.W117G (c.349T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 862346; https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W117G (c.349T>G)

MultipleGeneVariants: N/A

PatientID: 43

KindredID: 15

Case: F , 21Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (oatient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52.

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0002666; HP:0009711 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseHPOFreeText: The proband's daughter (patient 43) presented with retinal angioma at 17, multiple pancreatic cysts/tumors at 18, pheochromocytoma at 19, and renal cell carcinoma at 21.

CaseNotHPOs: HP:0010797 (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: p.S80Tfs*77 (c.239_245del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189246; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239_245del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239_245del)

MultipleGeneVariants: N/A

PatientID: 131

KindredID: 49

Case: F, Age 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0005584; HP:0001737; HP:0001732; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

CaseHPOFreeText: The proband presented with a pheochromocytoma at 18, retinal angioma at 29, and renal cell carcinoma and multiple pancreatic cysts/tumors at 31.

CaseNotHPOs: HP:0010797 (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: p.F136C (c.407T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496065; https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

PatientID: 2 (Brother)

KindredID: 3

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 3 members of this family were genetically confirmed to be carriers of a germline partial deletion of exon 2 of the VHL gene. ID 8 presented with CNS hemangioblastoma. ID 1 was asymptomatic. ID 16 presented with a retinal angioma (33Y), CNS hemangioblastoma at (32Y) and died at age 42. ID 16 was stated as having the germline variant but this was inferred from family/personal history and was not genetically confirmed.

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

CaseHPOFreeText: The patient presented with a retinal angioma (18Y) and pancreatic cyst or tumor (unspecified) (18Y).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: Exon 2 Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Partial deletion of Exon 2)

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: 7

KindredID: 3

Case: F, 18Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: Another member of this family (Gen 1) presented with the same mutation and bilateral pheochromocytoma, pancreatic cysts, RCC and neural hemangioblastoma.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0002668; HP:0030405; HP:0001737 (Pheochromocytoma, Hemangioblastoma, Paraganglioma, Pancreatic endocrine tumor, Pancreatic cysts)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma. Cause of death: adrenal crisis.

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 4

Case: Sex Unknown, 44Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other family members were found to have the same mutation (Patient 7,8,9,10).

CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405, HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient was diagnosed with pancreatic endocrine tumor at age 44 and diagnosed with pheochromocytoma and paraganglioma at age 18.

CaseNotHPOs: HP:0009711, HP:0001737, HP:0000107, HP:0005584 (retinal capillary hemangioma, pancreatic cysts, renal cyst, renal cell carcinoma)

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.500 G >A)

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: F, 18Y, Indian

DiseaseAssertion: assumed VHL

FamilyInfo: A detailed family history revealed the occurrence of central nervous system (CNS) tumors in her father and two of his siblings. Her father had recurrence of spinal tumors, adrenal masses, paraplegia, and eventually died following a cerebrovascular accident. His two brothers underwent surgery for cerebellar hemangioblastomas at age 46 and 50 years. The subject has two siblings aged 17 and 20 years, both of whom had no symptoms suggestive of VHL. No other members have been tested.

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0001085 (adrenal pheochromocytoma, pancreatic endocrine tumour, Papilledema)

CaseHPOFreeText: presented with recurrent episodes of headache for 3 years, associated with episodic sweating and palpitations. Fundus examination revealed bilateral papilledema (right adrenal mass with patchy peripheral enhancement, a smaller left adrenal mass (bilateral pheochromocytoma) and an enhancing lesion in the distal body of the pancreas)

CaseNotHPOs: N/A

CaseNotHPOFreeText: Her neurological examination was normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+3A>G

LegacyVariant: c.IVS2+3A>G

CaseProblemVariantFreeText: N/A

ClinVarID: 428796 https://www.ncbi.nlm.nih.gov/clinvar/variation/428796/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Region (c.463+3A>G)

MultipleGeneVariants: N/A

PatientID: None (Cousin 1)

KindredID: G

Case: Sex Unknown, 37Y0M, Hungarian

DiseaseAssertion: Assumed VHL

FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

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

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 37 and retinal hemangioblastoma at age 18. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

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: Variant reported as S80I and cDNA change was mapped to c.239G>T.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 107

KindredID: 36

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother presented with a CNS hemangioblastoma and retinal angioma at age 29, but passed away before the mutation could be confirmed.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma and retinal angioma at age 18.

CaseNotHPOs: HP:0005584; HP:0001737; HP:0001732; HP:0002666 (Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, 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.H110Pfs*49 (c.329delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 560741, https://www.ncbi.nlm.nih.gov/clinvar/variation/560741/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H110PFS*49 (c.329delA)

MultipleGeneVariants: N/A

GroupID: 33

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 the following mutation belonging to 2 families altogether. 

GroupPresentingHPOs: HP:0006880; HP:0005584; HP:0009711 (cerebellar hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)

GroupHPOFreeText: 1 patient had retinal angiomas diagnosed at age 18Y, 3 had cerebellar hemangioblastomas diagnosed at mean age of 18Y, and 1 had RCC diagnosed at 50Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R176Gfs*26 (c.526delA) 

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: R176fs (c.526del) 

MultipleGeneVariants: N/A

GroupID: 70

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.395A>C) was found in 1 VHL family with 2 patients.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0005584 (retinal capillary hemangioma; cerebellar hemangioblastoma; renal cell carcinoma)

GroupHPOFreeText: 1/2 patient had cerebellar hemangioblastoma (CHB) at 18Y, 1/2 had retinal capillary hemangioma (RH) at 37Y, and 1/2 had RCC at 49Y. Unclear as to which of the two patients these HPOs are paired to.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Q132P (c.395A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496063 https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Q132P (c.395A>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo:

CasePresentingHPOs: HP:0002666; HP:0001028 (Pheochromocytoma, Hemangioma)

CaseHPOFreeText: Was diagnosed with bilateral pheochromocytoma resected when she was the age of 18 years. She presented several relapses, the most recent one at the age of 32, when she was also diagnosed with cerebral angioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82G (c.244C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1297059, https://www.ncbi.nlm.nih.gov/clinvar/variation/1297059/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82G (c.244C>G)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: F, 18Y, Spanish

DiseaseAssertion: pheochromocytoma

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, brother, father, aunt and two cousins all showed positive for the familial mutation.

CasePresentingHPOs: HP:0002666 (adrenal pheochromocytoma)

CaseHPOFreeText: born in 1969, passed in 1987 at 18Y and had left (12cm) and right (14cm) adrenal pheochromocytoma tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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: This mutation was assumed due to the patient’s young age of pheochromocytoma, and family history. Originally, this patient had a suggested clinical diagnosis of MEN2A due to the presence of incidental thyroid C-cell hyperplasia found. However, family screening for medullary thyroid carcinoma (with CEA) failed to detect any abnormalities.

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: Sex Unknown, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's father had a hemangioblastoma of the central nervous system at age 45. He was deceased before diagnosis could occur. The patient's sister, daughter, and nephew were all confirmed to have the same genetic mutation but were asymptomatic.

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

CaseHPOFreeText: The patient presented with hemangioblastoma at age 18. Later at age 31, he/she presented with renal cell carcinoma and pancreatic cysts or tumours.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0009715 (retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: The patient did not have epididymal or ovarian cystadenoma.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: 8

Case: Unknown, 24Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

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

CaseHPOFreeText:The patient presented with hemangioblastoma at age 18. At age 24 the patient had renal cell carcinoma and cysts/tumours of the pancreas.

CaseNotHPOs: HP:0009711, HP:0002666(retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.W117S(c.350G>C)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117S(c.350G>C)

MultipleGeneVariants: N/A

PatientID: 17

KindredID: 17

Case: M, 18Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient was found to have multiple benign tumours 2 cm in size in her adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHC/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2 Loss

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had LOH of SDHC as indicated by Table 1.

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

PatientID:6

KindredID: 1

Case: F, 21Y0M, Ethnicity Unknown

DiseaseAssertion: Hemangioblastoma

FamilyInfo: Another member of the patients family (patient 1) had the same VHL gene mutation and presented with hemangioblastoma.

CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient presented with splenium of corpus callosum at age 18. The patient was followed up 37 months later.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T105P(c.313A>C)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496055 https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:T105P(c.313A>C)

MultipleGeneVariants:N/A

PatientID: 88 (Second cousin)

KindredID: 18

Case: F, 52Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed 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:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (18Y) and pheochromocytoma (17Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0009711 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Retinal capillary hemangioma)

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: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial 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: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 49 (Cousin)

KindredID: 18

Case: F, 62Y0M, 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:0002666; HP:0009711; HP:0005584; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: This patient presented with retinal angioma (18Y) and pheochromocytoma (20Y). Age of diagnosis of CNS hemangioblastoma and renal cell carcinoma is unknown.

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

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: 147

KindredID: 53

Case: F, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother presented with a CNS hemangioblastoma at age 17. She passed away before she could be diagnosed/ genetically confirmed with the same mutation as her daughter.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 18.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, 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: c.464-1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43603, https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>A)

MultipleGeneVariants: N/A

PatientID: 124

KindredID: 44

Case: M, Age 24Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 18, renal cell carcinoma and multiple pancreatic cysts/tumors at 24.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID: 24581539) and 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.W117S (c.350G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117S (c.350G>C)

MultipleGeneVariants: N/A

GroupID: 10

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 47.0Y +/- 18.4Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 6 members total were described, and phenotypic information was given for this group.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

GroupHPOFreeText: 3 of the 6 members presented with CNS hemangioblastoma (mean age of 40.0Y), 3/6 had retinal capillary hemangiomas (at a mean age of 23Y), renal cell carcinoma in 3 members (at a mean age of 35.3Y), pancreatic cysts in 2 members (with age of onsets of 26 and 27Y), and 1 with a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) (at age 18Y).

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: no members were found with pheochromocytomas

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336

SupplementalData: N/A

Variant: p.R113* (c.337C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113* (c.337C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother with the same variant and presented with breast cancer at age 46 and cerebellar hemangioblastoma and renal cell carcinoma both at age 54. Maternal grandfather (id: 3) presented with cerebellar hemangioblastoma at age 65. Maternal great-uncle (id: 4) presented with prostate cancer at age 65. Maternal great-grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Maternal grandmother and sister did not have the mutation. His maternal grandfather was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0005562 (Cerebellar hemangioblastoma, Spinal hemangioblastoma, Multiple renal cysts)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

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: Germline, FANCD2, Partial Deletion

PatientID: 7

KindredID: 7

Case: F, 26Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history of VHL.

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

CasePresentingHPOs: HP:0000618; HP:0009711; HP:0010797; HP:0002668 (blindness, retinal capillary hemangioma, hemangioblastoma, paraganglioma)

CaseHPOFreeText: At 15Y she presented with loss of visual acuity, leading to the diagnosis of bilateral retinal hemangioblastomas (treated with laser and cryotherapy), with the outcome of unilateral blindness. The patient was then operated 3 times for CNS hemangioblastomas between ages 18 and 24. At age 26, she presented with a palpable lateral neck mass. CT of the head and neck revealed a 3-cm carotid body tumor (paraganglioma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T105P (c.313A>C)

LegacyVariant: p.T105P

CaseProblemVariantFreeText: As the publication only provides the p., the mutation was deduced to p.T105P (c.313A>C)

ClinVarID: 496055 https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: T105P (c.313A>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: F, 18Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0010797; HP:0030405 (Pheochromocytoma; paraganglioma; hemangioblastoma; pancreatic endocrine tumor)

CaseHPOFreeText: Benign bilateral pheochromocytoma and sympathetic PGL, CNS hemangioblastoma and PNET at age 18

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

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: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: familial history of VHL disease

CasePresentingHPOs: HP:0030393; HP:0010797; HP:0001737 (endolymphatic sac tumor, hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: at 18Y experienced a sudden left hearing loss (MRI revealed hemangioblastomas of the temporal bone invading the otic capsule; operated on; the MTD of the endolymphatic sac tumor at diagnosis was 1.9 cm). The patient also developed pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Q (c.345C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496058 https://www.ncbi.nlm.nih.gov/clinvar/variation/496058/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: H115Q (c.345C>G)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: M, 18Y0M, Ethnicity Unknown

DiseaseAssertion: Cerebellar Hemangioblastoma

FamilyInfo: N/A

CohortInfo: The cohort included a series of 20 capillary haemangioblastomas of the central nervous system for mutations of the VHL gene.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183Cfs*19(c.548delC)

LegacyVariant: p.S183Cfs*19(c.761delC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795184 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.548delC

gnomAD: N/A

VariantEvidence: Refer to Table 1 for abnormal SSCP or heteroduplex patterns.

MutationType: minus_1_frameshift_variant

CivicName: S183fs (c.548delC)

MultipleGeneVariants: N/A

PatientID: F119

KindredID: 1

Case: F, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had a pheochromocytoma in the left adrenal gland. It was measured to be 3 cm in size and 23 grams in weight.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R64P(c.191G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A

When It Happens<br /> by [[Tom Ellison]] in McSweeney’s Internet Tendency<br /> accessed on 2026-04-18T08:30:46

令人震惊的时间预测：METR 认为 200 小时时间地平线的 AI 将在 12-18 个月内出现——也就是 2027 年底前。当前（2026 年初）最强模型约为 12 小时时间地平线，这意味着在不到两年内，AI 能独立完成的任务复杂度将提升约 17 倍。这不是科幻预言，而是 METR 基于实测数据的指数外推——而他们已经在为这个未来做组织准备了。

Ken’s influence didn’t appear as direct teaching, but changed the way he sees the world.

Being classified together as both Asian Americans will hide the real differences in their lives and experiences.

Circe sees Odysseus’s men as weak and easily scared. They try to look tough, but they still afraid of her power.

This shows that he is not a good soldier because he follows his own ideas, not orders. His thoughts about loyalty and honor make him different, but also cause problems.

Odysseus feels guilty and weak. Because he knows he can’t fight against a goddess’s anger.

Hsu Hua’s quiet writing style makes the story feel sincere and let the reader easy to connect with.

for - from - youtube - Just have a think - A controversial new paper challenges established emissions accounting criteria - https://hyp.is/9AQ6VF2SEfCsW8_68Y6AUA/www.youtube.com/watch?v=Y9f16OTL1Lg - climate crisis - ERF - agriculture 60% - fossil fuels 18% - agriculture is the biggest contributor to carbon emissions summary - This paper uses Effective Radiative Forcing (ERF) as a metric to measure global carbon emissions instead of the traditional Global Warming Potential (GWP) - It points out the problematic nature of GWP and how ERF provides a more accurate picture - Using ERF, the most surprising result of this study is that agriculture is the leading sector causing global warming - Measured from a baseline of emissions since 1750, - agriculture contributes 60% while - fossil fuels contributes 18% - Projects like Project Drawdown already prioritize agriculture, this gives even more validation and priority on transforming the agricultural sector - This also increases importance on efforts in: - regenerative farming - bioreginalism - permaculture - agroforestry - rewilding

This sounds like a story, because it is too fake in real life.

via u/Koponewt (Otto)

https://www.reddit.com/r/typewriters/comments/1l2ayq1/any_font_smaller_than_elite/

Die Grundschleppnetzfischerei erzeugt jährlich 370 Millionen Tonnen CO₂-Emissionen, doppelt so viel wie die Fischereiflotte selbst. Die meisten dieser Emissionen erreichen die Atmosphäre. Gut 40% bleiben im Wasser und tragen zur Versauerung bei. Eine neue Studie enthält erstmals genaue Daten zu diesen Emissionen. Im europäischen Parlament wird ein Verbot der Grundschleppnetzfischerei gerade blockiert. https://www.liberation.fr/environnement/climat/peche-climaticide-avec-le-chalutage-de-fond-le-co2-enfoui-dans-les-profondeurs-regagne-en-masse-latmosphere-20240118_EPWPRIYWQZEJNK2IOJW3LVGQHM/

Studie: https://www.frontiersin.org/articles/10.3389/fmars.2023.1125137/full

Though use make you apt to kill me, Let not to that, self-murder added be, And sacrilege, three sins in killing three.

In line 16 and 17, the speaker essentially tells the listener that if they were to kill the flea, it would be a ot only self-murder, but the murder of three lives: their own, the speaker's, and the flea's. In line 18, the speaker places the flea on this holy pedestal, treating it as if it were sacred . By doing this, he makes it seem as though killing it would be a greater offense than it really is.

Laws of Hywel Dda by [[National Library of Wales]]

Laws of Hywel Dda by [[Friends of the National Libraries]]

What?!

No!??

I'm glad Federico likes the new Control Center. For exactly this reason, I can quite definitively say that its functionality for me as a control center has been drastically reduced. And I can't help but wonder - as I stumble through the multiple, scrolling, asymmetric pages of this new second Home Screen, with all my privilege, experience, and attention with the possible functions therein - how in the actual fuck normal, functional, this-is-my-cellular-telephone users are managing.

I still need a control center but now I have a second homescreen instead.

for - decolonisation conference - Dekoloniale Berlin Africa Conference - source: human rights watch - Africans and People of African Descent Call on Europe to Reckon with Their Colonial Legacies - 2024 , Nov 18

for - decolonisation - colonialism - legacy of - 140 year anniversary of the dark milestone of the Berlin Africa conference which began a new cycle of horror and institutionalised plundering and dehumanisation of Africa - source: human rights watch - Africans and People of African Descent Call on Europe to Reckon with Their Colonial Legacies - 2024 , Nov 18

// - summary - Reading this story has reminded me of a Stop Reset Go / Deep Humanity / Tipping Point Festival project idea - cosmolocal bottom up movement that creates a community-to-community sister city coupling for development between communities of global / local North and global / local South

Why/how in God's name of the fuck would it be limited to (effectively) a single device??

...Voice Memos does not need to be a DAW.

https://www.derstandard.at/story/3000000245264/top-forscher-keywan-riahi-ueber-oesterreichs-schuld-am-klimawandel

Tell us more! Who was Ezra Stiles, and what was he doing during this time period?

Cite your source(s)!

for - polycrisis - organized crime - Daily Maverick article - organized crime - Cape Town - How the state colludes with SA’s underworld in hidden web of organised crime – an expert view - Victoria O’Regan - 2024, Oct 18 - book - Man Alone: Mandela’s Top Cop – Exposing South Africa’s Ceaseless Sabotage - Daily Maverick journalist Caryn Dolley - 2024 - https://viahtml.hypothes.is/proxy/https://shop.dailymaverick.co.za/product/man-alone-mandelas-top-cop-exposing-south-africas-ceaseless-sabotage/?_gl=11mkyl5s_gcl_auODI2MTMxODEuMTcyNjI0MDAwMg.._gaNzQ5NDM3NzE0LjE3MjMxODY0NzY._ga_Y7XD5FHQVG*MTcyOTM1MjgwOS4xLjAuMTcyOTM1MjgxOS41MC4wLjkyNTE5MDk2OA..

summary - This article revolves around the research of South African crime reporter Caryn Dolley on the organized web of crime in South Africa - She discusses the nexus of - trans-national drug cartels - local Cape Town gangs - South African state collusion with gangs - in her new book: Man Alone: Mandela's Top Cop - Exposing South Africa's Ceaseless Sabotage - It illustrates how on-the-ground efforts to fight crime are failing because they do not effectively address this criminal nexus - The book follows the life of retired top police investigator Andre Lincoln whose expose paints the deep level of criminal activity spanning government, trans-national criminal networks and local gangs - Such organized crime takes a huge toll on society and is an important contributor to the polycrisis. - Non-linear approaches are necessary to tackle this systemic problem - One possibility is a trans-national citizen-led effort

DOI: 10.1364/BOE.473237

Resource: (ZFIN Cat# ZDB-GENO-990423-18,RRID:ZFIN_ZDB-GENO-990423-18)

Curator: @olekpark

SciCrunch record: RRID:ZFIN_ZDB-GENO-990423-18

What is this?

DOI: 10.1016/j.crmeth.2023.100441

Resource: (ZFIN Cat# ZDB-GENO-990423-18,RRID:ZFIN_ZDB-GENO-990423-18)

Curator: @olekpark

SciCrunch record: RRID:ZFIN_ZDB-GENO-990423-18

What is this?

for - definition - Nature's Contribution to People - 18 categories

definition - Nature's Contribution to People - 18 categories

• Regulating Contributions -These are the services provided by nature that regulate environmental conditions.

  • Climate regulation
  • Air and water purification
  • Flood and disaster regulation
  • Disease regulation
  • Pollination
  • Pest and disease control

• Material Contributions - These are the tangible products obtained from nature.

  • Food and fiber
  • Freshwater
  • Genetic resources
  • Wood, fuel, and other materials
  • Medicines
  • Energy

• Non-material Contributions - These are the intangible benefits derived from nature.

  • Cultural identity and spiritual inspiration
  • Recreation and ecotourism
  • Aesthetic experiences
  • Knowledge and education
  • Sense of place and belonging
  • Mental and physical health

DOI: 10.1128/MCB.00581-18

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @bpowell22

SciCrunch record: RRID:SCR_006457

What is this?

https://www.reddit.com/r/typewriters/comments/17jvg8p/the_everest_model_90_with_a_reaaally_small/#lightbox

https://www.reddit.com/r/typewriters/comments/1dz7kdy/is_this_really_the_smallest_typeface_ever_made/

I've heard of Olympia SG1s with 17 CPI typefaces and some seem to think that 20 CPI machines may exist.

for - stats - U.S. working class - 666.1% of civilian workforce between 18 and 64

https://www.liberation.fr/environnement/climat/la-societe-generale-veut-reduire-de-50-ses-investissements-dans-les-hydrocarbures-dici-a-2025-20230918_PSHBQZT6UNDYVFHJ4ZGPINTOSM/

Ausführliche Berichte thematisieren die großen Hindernisse, die in Frankreich für die just transition zu einem nachhaltigen Leben bestehen. Die Klimakrise wird in allen Schichten als Bedrohung wahrgenommen, aber in den ärmeren Gruppen sieht man viel weniger Handlungsmöglichkeiten. https://www.liberation.fr/idees-et-debats/fin-du-monde-ou-fin-de-mois-quels-sont-les-freins-a-la-conversion-ecologique-des-classes-populaires-20231118_72LRGBQFONDVFJJY26JU5X2JQY/

Bericht des Wirtschafts-, Sozial- und Umweltrates: https://www.lecese.fr/sites/default/files/pdf/Avis/2023/2023_24_RAEF.pdf

Bericht des Wirtschaftsinstituts für das Klima: https://www.i4ce.org/publication/transition-est-elle-accessible-a-tous-les-menages-climat/

Die französische Regierung nimmt angekündigte Schritte zu einer schnelleren ökologischen Steuerreform zurück. So hält sie im Entwurf des kommenden Haushalts an der Subventionierung von Diesel für Lastwagen und von Flugbenzin fest.

https://www.liberation.fr/economie/fiscalite-verte-lexecutif-retropedale-dans-la-semoule-20230918_ZNS2IXMAQBA5FJNORUTVBS6THU/

Unter spanischer Vermittlung haben sich Frankreich und Deutschland auf Regeln für Energie-Subventionen geeinigt. Sie erlauben Frankreich, eine Mindestmenge an Nuklearstrom mit den bestehenden Kraftwerken zu produzieren, privilegieren aber erneuerbare Energie. Italien setzt bis 2050 auf Stromproduktion mit Erdgas. https://www.repubblica.it/economia/2023/10/18/news/energia_bollette_nucleare_rinnovabili_francia_germania-418138634/

Der Chefredakteur der Repubblica, Maurizio Molinari, setzt auf lösungsorientierten Klimajournalismus. Artikel zu Klimathemen, die Lösungen beschreiben, würden auch von Jüngeren gelesen. Bericht über eine Diskussion zum Klimajournalismus in Mailand. https://milano.repubblica.it/cronaca/2023/11/18/news/rapporto_tra_scienza_e_giornalismo_molinari_le_soluzioni_sono_il_futuro_dell_informazione_sul_cambiamento_climatico-420686220/

Eine extreme Hitzewelle hat in der Sahelzone Hunderte, wahrscheinlich Tausende Menschenleben gefordert. World Weather Attribution zufolge ist die Höhe der Temperaturen eindeutig auf die globale Erhitzung durch Treibhausgase zurückzuführen. https://www.theguardian.com/environment/2024/apr/18/lethal-heatwave-in-sahel-worsened-by-fossil-fuel-burning-study-finds

Zur Studie: https://www.worldweatherattribution.org/extreme-sahel-heatwave-that-hit-highly-vulnerable-population-at-the-end-of-ramadan-would-not-have-occurred-without-climate-change/

https://www.derstandard.at/story/3000000216428/ein-drittel-der-bevoelkerung-chinas-lebt-in-sinkenden-staedten

Der Amazonas-Regenwald kommt dem Kipppunkt, an dem er mehr CO2 abgibt als aufnimmt, immer näher. Eine neue Studie sagt vorraus, dass bis 2050 47% des Gebietes geschädigt sein könnten. Von Juni bis Dezember 2023 herrschte dort eine externe Dürre, die einer Attributionsstudie zufolge durch die globale Erhitzung 30mal wahrscheinlicher wurde. https://taz.de/Klimawandel/!5990314/

Studie: https://www.nature.com/articles/s41586-023-06970-0

Attributionsstudie: https://www.worldweatherattribution.org/climate-change-not-el-nino-main-driver-of-exceptional-drought-in-highly-vulnerable-amazon-river-basin/

Description of James Edward Oglethorpe

https://taz.de/Entscheidung-ueber-neuen-Nationalpark/!5996161/

https://taz.de/Import-des-gruenen-Wasserstoffs/!5996191/

https://www.derstandard.de/story/3000000212194/gefuehlte-temperatur-in-brasilien-bei-ueber-62-grad

https://www.theguardian.com/environment/2024/mar/18/banks-driving-increase-in-global-meat-and-dairy-production-report-finds

https://www.theguardian.com/world/2024/mar/18/south-sudan-closes-schools-in-preparation-for-45c-heatwave

https://www.theguardian.com/environment/2024/mar/18/bewildering-to-omit-meat-eating-reduction-from-un-climate-plan