PatientID: 2

KindredID: 2

Case: Sex Unknown, 33Y0M, Chinese

DiseaseAssertion: VHL

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

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 8

Case: M, 15Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma; paraganglioma; retinal capillary hemangioma)

CaseHPOFreeText: Benign sympathetic Paraganglioma at age 12Y0M and unilateral pheochromocytoma at age 15Y0M; as well as retinal angioma (age unclear)

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.Y98S (c.293A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 219160 https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y98S (c.293A>C)

MultipleGeneVariants: N/A

PatientID: 54

KindredID: 19

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: 115

KindredID: 42

Case: M, 12Y0M, 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:0009711; (Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 36, multiple pancreatic cysts and/or tumors at 40, and retinal angioma and renal cell carcinoma at 44.

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

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: 1 (case)

KindredID: 1

Case: F, 12Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Family history revealed that her mother had had bilateral partial adrenalectomy for pheochromocytoma during her youth; more recent follow-up investigations of the patient’s mother also revealed cerebral hemangioblastomas and a neuroendocrine tumor of the pancreatic head with liver metastases. She also showed the same mutation upon further follow-up.

CasePresentingHPOs: HP:0002666; HP:0030405 (pheochromocytoma; pancreatic endocrine tumour)

CaseHPOFreeText: Patient was affected for 1 year prior diagnosis by intermittent epigastric pains and diarrhea (clinical workup revealed a pancreatic tumor). Patient also showed a bilateral adrenal enlargement (pheochromocytoma - (11 mm right and 17 mm left)). There was no evidence of infiltration of the vena mesenterica superior. The mesentericoportal venous trunk and the large arterial vessels of the epigastrium were dissected from the tumor and preserved.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 12Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother had pheochromocytoma and positive family history of VHL.

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

CaseHPOFreeText: Retinoblastoma.

CaseNotHPOs: HP:0002668 (Paraganglioma)

CaseNotHPOFreeText: Criteria for exclusion were 1) absence of intra-adrenal tumor, 2) paragangliomas explicitly, 3) extra-adrenal secreting chromaffin tumors, 4) nonsecreting head–neck paragangliomas, 5) no operation, and 6) patients with normal levels of both urinary catecholamines and plasma metanephrines.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 2

Variant: p.G93D (c.278G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496054, https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was not significant for tumor occurrence.

CohortInfo: Two cases of VHL disease in children, who presented with PCC as the first manifestation.

CasePresentingHPOs: HP:0006748, HP:0030405 (Adrenal pheochromocytoma, pancreatic endocrine tumour)

CaseHPOFreeText: At age 10, abdominal MRI revealed a 44x33 mm mass with a necrotic core in the left adrenal gland. Subtotal adrenalectomy was performed and histologic examination showed that the tumor was PCC. During two years of follow-up, a 20x19x12 mm mass was detected in the right adrenal gland and a 11x10 mm nodular lesion in the corpus of the pancreas which was found to be a pancreatic endocrine tumour. One year later, the pancreatic endocrine tumour reoccured.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129P (c.386T>C) *the cDNA change is misrecorded in the paper as 386T>G

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625242 https://www.ncbi.nlm.nih.gov/clinvar/variation/625242/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L129P (c.386T>C)

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

KindredID: 15

Case: Sex Unknown, 53Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 other family members presented with the same VHL variant. Patient 15-I was asymptomatic. Patient 15-III presented with 2 pheochromocytoma (15Y).

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0009711 (Pheochromocytoma, Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 8Y. Presented with 2 pheochromocytoma (8Y) 2 CNS hb (12Y and 13Y) and 2 retinal hemangioblastomas (8Y, 12Y). Age at the end of study: 53Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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-1

KindredID: 1

Case: M, 36Y0M, Turkish

DiseaseAssertion: VHL

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s mother, brother, two daughters, and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405 (adrenal pheochromocytoma; renal cell carcinoma; pancreatic endocrine tumor)

CaseHPOFreeText: Right adrenal (nonfunctional) pheochromocytoma, had a history of bilateral adenomectomy due to bilateral pheochromocytoma diagnosed when he was 12. He also has bilateral RCC and pancreatic neuroendocrine tumors

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PatientID: VHL_17 (tumor ID)

KindredID: 17

Case: M, 12Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 12Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175N (c.523T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756226, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.523T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y175N (c.523T>A)

MultipleGeneVariants: N/A

PatientID: III:7

KindredID: 1

Case: M, 12Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Unilateral pheochromocytoma diagnosed at age 12.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 4

Case: M, 13Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: None

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

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

CaseHPOFreeText: The patient had a benign pheochromocytoma that was secreting norepinephrine at age 13. The patient had a retinal angioma and cerebellar hemangioma at age 12.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: Yes source unknown.

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, 19Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748; HP:0002666; HP:0030445; HP:0030405 (adrenal pheochromocytoma; pheochromocytoma; Pulmonary carcinoid tumor; Pancreatic endocrine tumor)

CaseHPOFreeText: At 12 years old, a female patient presented with fever and headache with high blood pressure. Upon a CT scan, a right adrenal tumor was detected and tumor resection was performed, revealing a pathological diagnosis of pheochromocytoma. Upon further review, a CT scan found multiple tumors in left adrenal and paraganglion region zones with round nodular shadows. She was diagnosed with pheochromocytoma (PCC) and paraganglioma (PGL). A lung puncture revealed a carcinoid and a pancreatic puncture indicates a neuroendocrine tumor. Left adrenalectomy and PPGL resection was performed and diagnosis was pathologically confirmed

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting:

PreviouslyPublished: N/A

SupplementalData: Yes (somatic info)

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: V-PH-05T

KindredID: 3

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No familial cancers/syndromic illnesses

CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangioma)

CaseHPOFreeText: diagnosed with recurrent phaeochromocytoma at age 12Y, surgery at 27Y. She also had a personal history of angioma of the right eye, laparotomy & numerous thyrocotomies, and a history of hypertension. Presence of elevated catecholamines, but no further details.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHA, SDHB, SDHC, TMEM127

PreviouslyPublished: 26796762

SupplementalData: Yes (see table S1 and S10)

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: Stated as ENSP00000256474.2:p.Thr157Ile

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: Germline, SDHA, c.113A>T (p.Asp38Val)

PatientID: 10

KindredID: 4

Case: M, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other family members were found to have the same mutation (Patients 6,7,8,9).

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

CaseHPOFreeText: The patient was diagnosed with a pancreatic endocrine tumor at age 13 it was found to be 0.7cm in size. He was diagnosed with pheochromocytoma and paraganglioma at age 12. He was found to have a right side pheochromocytoma measuring 5.5 cm and a left side pheochromocytoma measuring 1.5 cm. He was also found to have a paraganglioma measuring 2.2 cm.

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

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: IV

KindredID: 3

Case: Sex Unknown, 21Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 3 other family members presented with his VHL mutation. Patient 3-I was asymptomatic. Patients 3-II and 3-III both presented with pheochromocytoma at 15Y.

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

CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with pheochromocytoma at 12Y and retinal hemangioblastoma at 10Y. Age at the end of study: 21Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496054, https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s aunt presented with Hodgkin’s lymphoma at 38Y and was deceased at 40Y. The patient’s father presented with liver cancer at 72Y and was deceased at 74Y. Additionally, the patient’s deceased grandfather had an unspecified cancer. The patient’s son presented with unilateral pheochromocytoma at 13Y. The patient’s daughter presented with pheochromocytoma at 12Y, and bilateral retinal hemangioblastoma, right adrenal pheochromocytoma, and islet cell neuroendocrine carcinoma of the pancreas with nodal metastasis at 20Y, and was found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, retinal hemangioblastoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 12Y and retinal hemangioblastoma at 13Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.*214Lext*14(c.641G>T)

LegacyVariant: N/A

ClinVarID: 223236, http://www.ncbi.nlm.nih.gov/clinvar/variation/223236

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_loss

CivicName: *214Lext*14(c.641G>T)

MultipleGeneVariants: N/A

https://www.facebook.com/photo?fbid=10169712178549852&set=pcb.1384116267240477

Smith-Corona Sterling 12 typeface with foundry mark

https://www.reddit.com/r/typewriters/comments/1wse7lh/id_on_this_typewriter_from_twin_peaks/

<br /> Typewriter appears in Sheriff Truman's office

https://westcoastbelts.com/

Replacement belts for typewriters

This tracks with the Adler Meteor 12 from Soboroff's collection which is already documented on Richard Polt's page.

https://www.npr.org/2026/09/26/nx-s1-5979931/at-the-smithsonian-maya-angelous-typewriter-holds-a-place-of-honor

Voorkeuren en indifferentiecurven

PatientID: 10

KindredID: 10

Case: M, 22Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

CohortInfo: Case series of 14 patients with definite or presumed von Hippel-Lindau disease and retinal vascular proliferation.

CasePresentingHPOs: HP:0002011, HP:0001732, HP:0007850, HP:0012210, HP:0009711 (Morphological central nervous system abnormality, abnormality of the pancreas, retinal vascular proliferation, abnormal renal morphology, retinal capillary hemangioma)

CaseHPOFreeText: At age 12, his left eye had a large juxtapapillary vascular complex extending from the nerve along the superior arcade that was associated with dense fibrovascular tissue. During the next 29 months, this fibrovascular complex enlarged, extending into the center of the macula and causing a decrease in visual acuity to 20/80. The patient underwent pars plana vitrectomy and membrane peel. When the patient was reexamined 7 years after his surgery, there was no recurrence of the lesion. In the patient's contralateral right eye, 3 typical peripheral RCHs were observed during this 7-year follow-up. At age 14 years, he was also noted to have a small patch of superficial retinal vessels in the inferior retinal quadrant near the equator of the right eye that resembled an arteriovenous anastomosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: 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)

MultipleGeneVariants: N/A

Via Ted Munk at https://typewriterdatabase.com/1969-sears-medalist-power-12.24661.typewriter

Dinner for 12 Strangers: A Long-Standing UCLA Tradition<br /> by [[Michael Callahan]] Photos by [[Alyson Aliano]]<br /> accessed on 2026-05-07T11:02:33

Katie Fetterly, Typewriter Alliance <br /> Typewriter Collector<br /> eBay: https://www.ebay.com/usr/typewriter_alliance<br /> Instagram: https://www.instagram.com/typewriter_alliance/<br /> TWdB: https://typewriterdatabase.com/typewriters.php?hunter_search=5797

Has a collection of over 300+ typewriters in her home.

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。

Earlier intervention is reasonable when high-risk features are present, including rapid growth (≥0.5 cm/year), symptomatic aneurysm, saccular morphology, or penetrating atherosclerotic ulcers

reply to u/UsefulLength9143 at https://old.reddit.com/r/typewriters/comments/1ruew5h/royal_p_this_isnt_pics_font_is_it/

Looking closely at the slugs with letters, several clearly have a "P" foundry mark which was commonly used in this time period to identify Royal's "Royal Pica" face (see: https://typecast.munk.org/2011/04/24/1964-nomda-blue-book-royal-font-styles/) which was the generic name they gave in their catalogs to this particular pica (pitch) typeface. Similarly a foundry mark of "E" was often used to represent their 12 pitch "Royal Elite" typeface. Surely it's the case that the designer had some other name for this typeface, but I've never seen Royal documents which specify anything other than Royal Pica or Royal Elite.

While it certainly helps to see the rulers on the carriage to doublecheck, one can guess the exact typeface in this instance solely by the foundry marks, though this is not always the case for a wide number of manufacturers.

Generally people are right in asking to see the ruler as the difference in width of slug on a 10CPI and 12CPI machine is on the order of 1/64 of an inch which is incredibly hard to discern visually on photos like these without something to use for scale.

https://shopgoodwill.com/item/256505880

Previously bid up to $196 and abandoned: https://shopgoodwill.com/item/254909011

Looks like Remington Cubic 12 Pitch

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

wow the breakup trauma,they didn't end well

wow,tom told the truth to george,poor guy,but george doesn't seem to accept the truth

george start to accuse gastby as the murderer of his wife,i think hisa poor guy,everyone has been hiding secret from him.

Nick cares about Gatsby. He wants to make sure he is not alone. It also shows how abandoned Gatsby is at the end.

Gatsby’s hope was almost gone. Although he waited for the phone call, he likely knew it would never come. The call maybe symbolize the end of Gatsby’s dream.

Daisy’s decision was shaped by fear and pressure than by a lack of love. She need reassurance and stability, but Gatsby couldn’t give her at the time, this is the reason why she turned to Tom.

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.

This image shows the conflict between Daisy’s public elegance and her private distress. The letter suggests unresolved feelings that threaten her carefully arranged future. The wine in her hand reveals how overwhelmed she is by the choice she is about to make.

This moment shows how casually Gatsby uses personal influence to control the situation. It reduces the policeman’s authority to a simple gesture. It also reveals the hidden power Gatsby relies on beneath his glamorous image.

This question exposes Gatsby’s deep insecurity beneath his confident exterior. He needs validation to support the image he has carefully constructed. It also shows how fragile his persona becomes when he loses control of the narrative about himself.

Daisy and Gatsby liked each other and they cared for each other.

https://www.terrigivens.com/reckoning/

for - definition - anthropocene - synchronized signals of great acceleration at all 12 sites, not just Crawford Lake - Francine McCarthy, Brock University

https://www.goodreads.com/quotes/4857-ginny-said-mr-weasley-flabbergasted-haven-t-i-taught-you-anything

https://en.wikipedia.org/wiki/Emily_M._Bender

This sentence shows how fully Nick aligns himself with Gatsby in death, even more than in life. He feels a moral loyalty that the rest of Gatsby’s world refuses to offer. It also marks Nick’s final separation from the careless society he has been observing.

This sentence shows Gatsby’s growing fear that his dream cannot survive real contact with Daisy. He realizes that she cannot see the world he has built around her. It also exposes the emotional distance that his fantasy tried to hide.

This sentence shows how deeply Gatsby bases his self-worth on Daisy’s approval. His possessions stop being symbols of success and become tools for winning her reaction. It also reveals how unstable his dream is, because it depends entirely on her gaze.

This makes me realize that using specific words could make such a big difference.Adding small details like color or sound can suddenly make writing feel more alive.

https://www.typewriter.company/pt/products/rare-olivetti-typewriter-cartridge-ribbon-for-olivetti-lettera-10-12-lettercart-ribbon

It seems like the cartridges for the Lettera 12 are no longer available.

see also: https://www.reddit.com/r/typewriters/comments/1ov8fa3/olivetti_lettera_12/

SCM Electra 220 Versus Coronet Automatic 12 - YouTube<br /> by [[Joe Van Cleave]]<br /> accessed on 2025-11-01T22:48:53

The Coronet Automatics were one of the first in their line with 1/2 line spacing.

https://www.reddit.com/r/typewriters/comments/1o8lzdm/trying_to_id_a_typewriter_from_a_video_game/

Folklore (2007, PlayStation 3)

DOI: 10.1016/j.devcel.2025.07.011

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-171002-12

What is this?

Gwneud Cyflaith / Toffee Making by [[Amgueddfa Cymru]]

Kmart 300 Deluxe 12 Typewriter by [[Joe Van Cleave]]

Because of the geometry of the JP-7's ribbon vibrator, which hinges from the right rather from the middle, the ribbon can rub against the paper/platen. To remedy this, one can mis-thread the left side to keep the ribbon away from the paper.

This is a clone of a now-down page on HHS where President Clinton made remarks about privacy

News article on the release of the HIPAA privacy rules

This is the press release from the Clinton whitehouse on the release of the HIPAA privacy rule.

Bill Clinton discussing in simple terms the portions of HIPAA designed to ensure the medical records would be interoperable in a secure fashion.

These are the statements by President Bill Clinton on the release of the HIPAA Privacy Rule in 2000

This is the section of the CURES act that specifically mandates API based interoperability.

This is the second clause in the CURES act that mandates general standards-based health information exchange using the "without special effort" clause

SCM Electric Typewriters by [[Joe Van Cleave]]

Tips for cleaning the Smith-Corona 6 series electric typewriters and details about how they work.

S-C also made this series of typewriter for both Sears and Singer under their branding. (including the Singer Electric in this video.)

The belts on the electric motor and cams was originally a rubber 'V' belt which is no longer manufactured. Using 1/8" round cross-section o-rings of appropriate sizes (for water cannister applications) is the recommended replacement, however one may need to slightly move the drive motor down a bit so that the belt doesn't hit the frame of the typewriter and thereby destroying it over time.

Cleaning and lubricating the drive motors and moving pieces before using may help before trying out a typewriter which has been sitting for long periods of time.

Some later models had an electric return, which can tend to be violent. Electro 220 and Coronet Automatic 12 have an additional clutch and draw band (and lack of return lever on the carriage) for their electric returns.

Vor allem zu den finanziellen Verflechtungen der Trump-Familie mit den arabischen Petrostaaten.

https://www.nytimes.com/2025/05/12/us/politics/trump-middle-east-visit-saudi-arabia-qatar-uae.html

https://www.derstandard.at/story/3000000268965/vom-retter-zum-risiko-oesterreichs-wald-wird-fuers-klima-zum-problem

https://taz.de/Russland-auf-der-COP/!5978943/

Hannes Amesbauer (FPÖ) und andere beantragen, Extinction Rebellion und die Letzte Generation als „Klimaterroristen" geheimdienstlich observieren zu lassen.

https://www.parlament.gv.at/dokument/XXVII/A/3050/fnameorig_1489291.html

https://www.kleinezeitung.at/steiermark/19207990/der-klimaschutz-weicht-den-interessen-der-autofahrer

DOI: 10.1038/s41467-025-58821-3

Resource: None

Curator: @scibot

SciCrunch record: RRID:ZFIN_ZDB-ALT-111213-12

What is this?

This is a wonderful history of the NPI system.

The NPPES Privacy Impact Assesment.

This is the current SORN for NPPES. Does not appear to have changed since 2017.

"Pieter de Marees announced in 1602, for instance: 'the women here are of a cruder nature and stronger posture than the Females in our lands in Europe.'" p. 12

The masculinization of African/black women began even around the 16th and 17th century. Its' effects still reverberate in many of our American systems today (i.e. black women and pregnancy---Serena Williams popular example).

"...they [African women] have no need of midwives, doctors, nurses and I have known [African] women go to bed over night, bring forth a child and be abroad the next day by noon." p. 12

The same type of attitude is still held on to today and brings irreputable harm to black women in medicine more broadly as well as during pregnancy. In the present we have appointed officials such as Robert F. Kennedy Jr. who even repeats extraordinarily similar rhetoric.

"Still, the women 'were excellent,' possessed of a 'beauty no Painter can express.' p. 12

The clarification should be 'no white European painter could express' because the complexions and bodies of Africans were incongruent with the complexions and forms of bodies they would have been familiar with.

It reminds me that many of the subjects and items we interact with today always use someone (or a specific group of people) as the basis of the design or insights (i.e. how medicine identifies acceptable levels of pain-tolerance often on the basis of fairer complexions or how facial recognition tends to be more accurate with fairer complexions over darker ones); these are intentional and a result of who is used as the example or placeholder for medicine, technologies and so on.

for - program event selection - 2025 - April 3 - 12:30 - 1:45pm GMT - Skoll World Forum - The Future of Foreign Aid - Fellowship of the Sacred Commons - LCE - relevant to - funding the commons

https://www.nytimes.com/2025/03/12/climate/epa-zeldin-rollbacks-pollution.html

Zeigt, wie ich finde, sehr gut die Aporien und die Möglichkeiten einer linken Politik angesichts der Klimakrise. Dabei gibt es viele Bezüge zum Buch Klamot Leroyanfern. Wenn Wright sucht eine Position, jenseits einer im weitesten sind kinesianischen Politik und auch einer neoninistischen Politik. Es gibt viele Bezüge zu den Sapatisten und ähnlichen Bewegungen. Argument für eine radikal alternative Praxis ist, dass alle existierenden Politik die Klimakrise nicht aufhalten werden.

https://territories.substack.com/p/hell-is-truth-seen-too-late

https://www.liberation.fr/environnement/biodiversite/puits-de-carbone-et-oceans-le-plancton-tient-un-role-majeur-dans-la-regulation-du-climat-planetaire-a-long-terme-20231206_WPRTMTZ5H5BZJEELVRWFE3WBEI/

Breakthrough Energy, die Organisation welche dieKlima und energiepolitischen Aktivitäten Aktivitäten von Bill Gates bündelt, reduziert die Aktivitäten Ihres amerikanischen Policy-Teams dramatisch. Damit reagiert die Organisation auf die Politik der Trump-Administration, die die bisherige Form politischer Arbeit weigehend ineffizient macht. Gates will sich in Zukunft auf die Entwicklung von Firmen im Bereich saubere Energien konzentrieren. Diese Aktivitäten passen zu Trumps Ziel einer amerikanischen Energiedominanz. https://www.nytimes.com/2025/03/12/climate/bill-gates-breakthrough-energy-cuts.html?unlocked_article_code=1.3U4.gtug.AAWTHQIZC6Rj&smid=url-share

This flea is you and I, and this Our marriage bed, and marriage temple is;

The speaker tells the listener that the flea signifies their marriage bed and temple. By this logic, it sets the two being already married. By making the flea play the part of a temple and bed, it seemingly makes this small, insignificant bug, play a huge role within the poem.

Überblicksartikel von 2019 zu den Angriffen auf die Wissenschaft während der ersten Trump-Regierung und ihre kurz- und langfristigen Folgen. Forschungen zur Klimakrise und öffentlichen Gesundheit wurden behindert, weil sie den Interessen der fossilen Industrien schaden. Der Kampf gegen Foschung, die Interessen bestimmter Unternehmen und Branchen bedroht, ging aber weit über die Klimathematik hinaus und dient u.a. auch der Chemie- und Agroindustrien. Zu den Maßnahmen gehörten: - Beendigung von Forschungsprojekten - Abbau des Einflusses von Wissenschaftler:innen auf regulatorische Entscheidungen - Verhinderung von öffentlichen Stellungnahmen von Wissenschaftler:innen - Behinderung von Forschungen zum menschengemachten Klimawandel - Vorschreiben erwünschter Forschungsergebnisse - Overruling von Experten durch politische Funktionäre bei Begutachtungen und Regulierungen - Einstellungsstopps und Entlassungen - Entfernung bestimmter Wissenschaftler:innen aus Beratungsgremien - Verbot der Berücksichtigung bestimmter Wissenschaftstypen bei Regulierungen - Druck auf Forschende, unwissenschaftliche Aussagen des Präsidenten zu unterstützen - Schließung von Forschungszentren und -büros und Auflösung von Ausschüssen - Umsiedlungen von Behörden und Forschungseinrichtungen in unattraktive Gegenden

https://www.nytimes.com/2019/12/28/climate/trump-administration-war-on-science.html

> for - stats - addiction - rehab centers - 85% are based on disease model - and 85% use a religious oriented 12 step program

https://www.derstandard.at/story/3000000255432/wie-sehr-die-us-wissenschaft-unter-trump-leiden-koennte

https://www.derstandard.at/story/3000000252312/klimaforscherin-wir-wuerden-auch-in-kein-flugzeug-mit-zehnprozentigem-absturzrisiko-steigen

DOI: 10.1016/j.celrep.2024.115195

Resource: None

Curator: @sjvitug

SciCrunch record: RRID:ZFIN_ZDB-ALT-100504-12

What is this?

Der französische Klimatologe Robert Vautard stellt fest, dass die Temperaturen des Jahr 2024 noch stärker als 2023 vom Erwartet abgewichen sind. Seit zwei Jahren erlebe der Planet einen zusätzlichen Fieberschub. Die Gründe seien noch nicht geklärt, die Reduzierung der Reflexion von Sonneneinstrahlung durch die Abnahme des arktischen und antarktischen Meereises spiele wahrscheinlich eine Rolle. https://www.liberation.fr/environnement/climat/rechauffement-pour-le-copresident-du-giec-2024-a-ete-encore-plus-hors-norme-que-2023-et-cela-pose-beaucoup-de-questions-20241231_Q4A5ZQBEBRHWREZIY3UYGSFEFM/?redirected=1

Science-Studie zur Abnahme der Albedo der Erde: https://www.science.org/doi/10.1126/science.adq7280

这篇论文介绍了一个名为ROSCOE的度量标准套件，用于评估逐步骤推理的性能。ROSCOE是一套可解释的、无监督的自动评分系统，旨在改进和扩展之前的文本生成评估指标。该研究通过设计一个推理错误的分类学，并在常用的推理数据集上收集合成和人类评估分数，来评估ROSCOE相对于基线指标的表现

Der definitive Narionale Energies- und Klimaplan Österreichs wurde kurz vor Weihnachten von der Bundesregierung beschlossen und an die EU übermittelt. Der auch für kommende Regierungen verbindliche Plan sieht eine Reduzierung der Treibhausgas-Emissionen um 46 bis 48% bis 2030 vor. Streit in der Regierung hatte die Verabschiedung verzögert. Ein Ende des eingeleiteten Vertragsverletzungsverfahrens wird erwartet https://www.derstandard.at/story/3000000250184/-214sterreichischer-klimaplan-beschlossen-und-an-eu-252bermittelt