PatientID: DIII7

KindredID: D

Case: F, 16Y0M, Chinese

DiseaseAssertion: pancreatic cysts

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

CasePresentingHPOs: HP:0001737 (pancreatic cysts)

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

LegacyVariant: p.F76del (c.439delTCT)

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

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_2289delTCT)

MultipleGeneVariants: N/A

PatientID: 83 (Cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5 (Aunt)

KindredID: 17

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: deletion; minus_2_frameshift_variant

CivicName: V166SFS*4 (c.496_506del)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: F, 28Y0M, German

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 29Y0M, Brazilian

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: III-5

KindredID: Family A

Case: F, 32Y0M, Ethnicity unknown

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: III-2

KindredID: 1

Case: M, 16Y0M, ethnicity unknown

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0001901 (polycythemia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 1

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

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

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: III

KindredID: 17

Case: Sex Unknown, 26Y0M, Danish

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: I

KindredID: 7

Case: Sex Unknown, 40Y0M, Danish

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 1

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

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

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.695G>A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: II-a

KindredID: 1

Case: F, 16Y0M, Greek

DiseaseAssertion: Assumed VHL

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

gnomAD: N/A

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

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: II.6

KindredID: F8

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+648T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant;transition; splice_site_variant

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

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

PatientID: 4

KindredID: 4

Case: 16Y1M, sex unknown ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: None

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

CaseHPOFreeText: spinal hemangioma was cervical.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.341-1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: 16Y1M, sex unknown ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: None

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

CaseHPOFreeText: spinal hemangioma was cervical.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.341-1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

GroupID: 42

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

GroupID: 42

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Annotations <br /> alternate link for annotations

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

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

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

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

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

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

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

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

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

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

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

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

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.

https://www.derstandard.at/story/3000000253166/duerren-werden-kuenftig-oefter-mehrere-jahre-dauern

https://www.derstandard.at/story/3000000252943/la-nina-ist-endlich-da-mit-verspaetung-und-deutlich-schwaecher-als-erwartet

https://www.derstandard.at/story/3000000203337/214sterreichs-emissionen-sanken-2022-laut-uba-bilanz-um-58-prozent

Throw Out Your Black Plastic Spatula by [[Zoë Schlanger]]

Lots of links to journal articles and published studies here.

Find out more about this and describe what happened.

Cite your source(s)!

https://experiments.myhub.ai/ai4communities_post

Matthew Lowry experiment

for - rapid whole system change - Nafeez Ahmed - planetary phase shift - Nafeez Ahmed - planetary adaptive cycle - Nafeez Ahmed - essay - The End of Scarcity? From ‘Polycrisis’ to Planetary Phase Shift - Nafeez Ahmed - 2024 Oct 16 - to - book - The Ascent of Humanity - chapter 8 Self and Cosmos: The Gaian Birthing - stillborn and the perilous journey through the womb - Charles Eisenstein

summary - This is a good article that makes sense of the inflection point that humanity now faces as it contends with multiple existential crisis - It summarizes the complexity of our polycrisis and its precarity and lays the theory for looking at the polycrisis from a different perspective: - as a planetary phase shift towards the potential end of scarcity and the next stage of our species evolution - Through the lens of ecologist Crawford Stanley Holling's lens of the adaptive cycle of ecological population dynamics, - and especially his 2004 paper "From Complex Regions to Complex Worlds" - Nafeez extends Holling's argument that we are undergoing a planetary adaptive cycle in which the back-loop is the dying industrial era. - In this sense, it is reminiscent of the writings of Charles Eisenstein in his book "The Ascent of Humanity", chapter 8: Self and Cosmos:, The Gaian Birth. - Eisenstein uses the the perilous journey of birth through the womb door as a metaphor of the transition we are currently undergoing.

to - paper - From Complex Regions to Complex Worlds - Crawford Stanley Holling - 2004 - https://hyp.is/KYCm2pFrEe-_PEu84xshXw/www.ecologyandsociety.org/vol9/iss1/art11/main.html?ref=ageoftransformation.org - book - The Ascent of Humanity - Chapter 8 - The Gaian Birthing - Charles Eisenstein - https://hyp.is/r8scTpG_Ee-gLTujlli5hQ/charleseisenstein.org/books/the-ascent-of-humanity/eng/the-gaian-birthing/

for - Adrian Bejan - constructal law - childhood - art and science - from - The End of Scarcity? From ‘Polycrisis’ to Planetary Phase Shift - Nafeez Ahmed - 2024, Oct 16

Summary - Good explainer video about constructal theory and flow

from - The End of Scarcity? From ‘Polycrisis’ to Planetary Phase Shift - Nafeez Ahmed - 2024, Oct 16 - https://hyp.is/Qt8IMI74Ee--f4O18QMPFQ/ageoftransformation.org/the-end-of-scarcity-from-polycrisis-to-planetary-phase-shift/

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

non-existent towns and streets used to trap plagiarists

Relation to Genius.com's trap of Google on music lyrics

Die großen US-Investmentgesellschaften BlackRock, JPMorgan Chase und State Street haben sich zu großen Teilen aus der Koalition Climate Action 100+ zurückgezogen, in der sich Unternehmen zur Dekarbonisierung verpflichten. Damit werden dieser Koalition 14 Billionen (14.000 Millionen) Dollar entzogen. Republikanische Politiker:innen versuchen schon länger zu verhindern, dass Investionen an Dekarbonisierungszusagen gebunden werden. Die Investment-Gesellschaften argumentieren jetzt, dass Climate Action 100+ nicht nur eine Offenlegung fossiler Investionen, sondern eine Steuerung verlangt habe. https://www.nytimes.com/2024/02/16/business/dealbook/wall-streets-climate-retreat.html

Das französische Komitee für die Biodiversität beurteilt die aktualisierte Biodiversitätsstrategie der Regierung positiv, weist aber zugleich auf Defizite hin. So werden nicht alle Aspekte des Abkommens von Kunming-Montréal umgesetzt, obwohl es von Frankreich unterzeichnet wurde. Für die Biodiversität schädliche Subventionen, insbesondere bei der gemeinsamen Agrarpolitik der EU, werden nicht abgeschafft. https://www.liberation.fr/environnement/biodiversite/strategie-nationale-biodiversite-du-gouvernement-du-bon-mais-peut-mieux-faire-20231016_2VTD2OM2OVDH3HWKD7NNWUN4IU/

Norwegen erteilt in diesem Jahr 62 Lizenzen für die Exploration von Öl- und Gasfeldern, gegenüber 47 im vergangenen Jahr. Die Steigerung geht auf das Interesse von Öl- und Gasgesellschaften zurück. Gegen den Widerstand von NGOs betreibt Norwegen weiterhin eine Ausweitung der Öl- und Gasproduktion, die zu jahrzehntelanger Förderung führen soll. Stark gewachsen ist dabei das Interesse an der Barents Sea. https://www.reuters.com/business/energy/norway-increases-number-new-oil-gas-drilling-permits-including-arctic-2024-01-16/

https://www.theguardian.com/us-news/2023/jul/16/big-oil-climate-pledges-extreme-heat-fossil-fuel

Maintenance Of Office Machines. 16 mm. Vol. MN-1513. United States Navy Training Film, 1943. https://www.youtube.com/watch?v=ocdxgkxKAKo.

Should be "crustose"

https://www.theguardian.com/world/2024/apr/16/which-uk-foods-are-at-risk-as-extreme-weather-causes-havoc-with-global-supplies

In Frankreich hat es seit 26 Tagen nicht geregnet. Die Trockenheit - möglicherweise wird Frankreich den trockensten September seit den 1950er-Jahren verzeichnen, verschärft die Folgen der 9-monatigen Rekord-Trockenheit im vergangenen Jahr.

Italien hat in den ersten beiden Monaten dieses Jahres 2,9 Milliarden Kubikmeter Erdgas LMG Transporte erhalten Punkt das sind mehr zum ersten Mal mehr als via Pipeline aus Algerien geliefert wurde. Der der Anteil des russischen erdgases fiel von 40% 20 21 auf 4,7% 2023. Die Infrastruktur für die Anlieferung von LNG wird auf fünf große Anlagen ausgebaut. Insgesamt ist der Gasverbrauch vor allem wegen der milden Winter um 10% gesunken. https://www.repubblica.it/economia/2024/03/16/news/gas_gnl_rigassificatori_gasdotti_russia-422324021/

https://victorianweb.org/

https://www.theguardian.com/environment/2024/mar/16/climate-activists-across-europe-block-access-to-north-sea-oil-infrastructure

I have the opposite of low hums, I hear incredibly high-pitched sounds. This video contains one of those frequencies. CRT monitors and other tube TVs are incredibly loud to me even if the volume is off.

same here, tinnitus at 16 KHz. i guess this comes primarily from the power grid, because when i measure my body skin voltage versus power ground, via microphone port of a smartphone and spectrogram app, then i see the noise around 16 KHz. i guess the source are power electronics connected to the power grid, especially IGBT transistors which have a working frequency around 16 KHz. i spent 2000 euros on EMF shielding for my bedroom (YShield HNV80), but that can only shield high frequencies like 2.4 GHz wifi, but not the low frequencies from the power grid - 50 Hz to 16 KHz. i started hearing this after a LSD trip... expanding ones consciousness in a bad setting is a bad idea

Preisentwicklungen auf dem Ölmarkt werden zunehmend vom algorithmischen Handel beeinflusst, also von Kauf- und Verkaufsempfehlungen von Computern in Verbindung mit dem Handel von Derivaten. Wie relevant die "Commodity Trading Advisors" (CTAs), die meist computergesteuert und mit regelbasierten Strategen arbeiten, bereits sind, ist umstritten. Hintergrundbericht im Handelsblatt. https://www.handelsblatt.com/finanzen/maerkte/devisen-rohstoffe/ctas-die-unheimliche-macht-auf-dem-oelmarkt-und-was-dahintersteckt/100008536.html

https://www.derstandard.de/story/3000000207802/mehrheit-hat-angst-vor-klimakrise-aber-weiss-nicht-was-sie-tun-soll

https://www.derstandard.de/story/3000000207635/bewaldungsprogramm-in-afrika-zerstoert-intakte-oekosysteme

5 europäische NGOs wollen erreichen, dass die neue europäische Taxonomie nicht länger erlaubt, Investitionen in mit fossilen Treibstoffen betriebene Schiffen und Flugzeuge als nachhaltig zu labeln. https://www.derstandard.at/story/3000000203249/ngos-fechten-gruenes-eu-label-fuer-flugzeuge-und-schiffe-an

Großbritannien will die Kapazitäten seiner Atomkraftwerke bis 2050 auf 24 GW steigern. Von Angie aus werden diese Pläne auch kritisiert weil die Kosten der Atomenergie enorm hoch sind. https://www.repubblica.it/economia/rapporti/energitalia/trasformazione/2024/01/16/news/la_gran_bretagna_punta_sullenergia_nucleare-421889343/

Anwälte, die eng mit Charles Koch und Koch Industries verbunden sind, unterstützen vor dem Supreme Court der USA Fischer, die gegen Fangbeschränkungen durch eine Umweltbehörde klagen. Ziel ist, dass Bundesbehörden auch die Fossilindustrie und andere Bereiche der Wirtschaft nicht mehr wirksam kontrollieren können. https://www.nytimes.com/2024/01/16/climate/koch-chevron-deference-supreme-court.html

Deutschland wird in dieser Legislaturperiode kein Klimageld auszahlen, obwohl der CO₂-Preis steigt. Fachleute kritisieren die Streichung der Maßnahme, u.a. weil damit auf sozialen Ausgleich verzichtet wird. https://taz.de/Ampelkoalition-verschiebt-Ausschuettung/!5986234/

https://www.repubblica.it/green-and-blue/2024/01/16/news/davos_world_economic_forum_cambiamenti_climatici_morti-421887165/

Der Standard fasst Berichte der WMO, des europäischen Wetterdienstes Copernicus und des Österreichischen Alpenvereins zum Schwund der Gletscher 2022 zusammen. Die europäischen Alpengletscher verloren 2022 mehr als 5 Kubikkilometer Eis. Die Schweizer Alpengletscher haben in 20 Jahren ein Drittel ihres Eises eingebüßt. Bei einer Temperaturerhöhung um 2,7° bis 2100 würde allein durch das fast vollständige Abschmelzen der Gletscher in Mitteleuropa, den USA, Westkanada und Neuseeland der Meeresspiegel um 115mm steigen.

https://www.derstandard.de/story/2000145833249/die-gletscher-schmolzen-2022-im-rekordtempo-besonders-in-europa

Infografik: https://b.staticfiles.at/elm/static/2023-04-schneeanomalie/index.html?nc9238cb923b983a

Seit 2019 hat sich die Zahl der Malaria Kranken weltweit von um 20 Millionen auf 249 Millionen im Jahr erhöht Punkt ein Hauptgrund dafür sind die Folgen der globalen Erhitzung. In Pakistan sind nach dem großen Überschwemmungen des vergangenen Jahres mehr Menschen an Malaria gestorben, als den Überflutungen direkt zuvor zum Opfer gefallen sind Punkt Interview mit...https://www.liberation.fr/international/paludisme-les-phenomenes-meteorologiques-extremes-provoquent-une-recrudescence-des-cas-20231216_QIG4KWG4NRHZ3CT5GYQKEO6K2Y/

Der Deutsche Bundestag hat ein Klimaanpassungsgesetz beschlossen. Es verpflichtet Bun,d Länder und Gemeinden zu vorsorglicher Klimaanpassung und dazu, die Klimaanpassung bei allen Maßnahmen zu berücksichtigen. Noch unklar ist die Finanzierung. https://taz.de/Klimaanpassungsgesetz-im-Bundestag/!5969940/

https://shindig.com/login/event/gutkin

What kind of teacher do you think has this kind of impact?

What does this communication look like?

This is a critique with a priority being placed on data based decisions.

Wow, this seems like it would require a drastic change in school environments.

I wonder what the connection will be between motivation and assessment!

Ein Kommentar in der New York Times weist daraufhin, dass einer der Hauptgründe für das für die geringe Nutzung erneuerbarer Energien die veralteten stromübertragungsnetze sind. In den USA scheitert ihre Erneuerung an den Kosten bzw der mangelnden Bereitschaft, für Sie die Allgemeinheit aufkommen zu lassen Punkt der Artikel erwähnt ähnliche Probleme in Deutschland wo Strom von windkraftwerken im Norden mangelsleitungen nicht nach Süddeutschland transportiert werden kann