GroupID: 77

Case: 23Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.491A>G) was found in 1 VHL family with a single patient.

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

CaseHPOFreeText: patient had pheochromocytoma diagnosed at 10Y, a retinal angioma at 23Y.

CaseNotHPOs: HP:0005584; HP:0006880 (renal cell carcinoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Q164R (c.491A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2238 https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q164R (c.491A>G)

MultipleGeneVariants: N/A

PatientID: III-3

KindredID: 1

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family in India but Ethnicity not explicitly confirmed. Father and sister with the same mutation. Sister presented at age 17 with palpitation, blurred vision, blurring vision, bilateral papilledema and bilateral pheochromocytoma. Father presented at age 14 with hypertension and a right adrenal pheochromocytoma. He had severe headache, recurrent seizures, abnormal heart sounds and recurring pheochromocytoma in the left hypochondrium at age 22. Mother and uncle were negative for the mutation.

CasePresentingHPOs: HP:0002666; HP:0002315 (Pheochromocytoma, Hypertension)

CaseHPOFreeText: Presented at 10 years of age with severe hypertension. He was found to have bilateral pheochromocytoma. Asymptomatic at age 25.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.R82L (c.245G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors carried out analysis of VHL variant p.Arg82Leu with six different in silico tools namely SIFT, I-Mutant3, PhD-SNP, MutPred, PolyPhen2 and SNPs&GO in order to determine the pathogenic potential of the variant.

MutationType: missense_variant;transversion

CivicName: R82L (c.245G>T)

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: 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: 27

KindredID: 19

Case: M, 14Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: They had a 47Y family member (ID:26), however their relation is unclear.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient at 10Y was confirmed with VHL. He developed bilateral pheo at 10Y with recurrence 48M later.

CaseNotHPOs: HP:0002668; HP:0001737; HP:0010797; HP:0005584; HP:0030405; HP:0009711; HP:0000107 (paraganglioma, pancreatic cyst, hemangioblastoma, renal cell carcinoma, pancreatic endocrine tumor, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T124I (c.371C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 36902 https://www.ncbi.nlm.nih.gov/clinvar/variation/36902/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T124I (c.371C>T)

MultipleGeneVariants: N/A

PatientID: II.7

KindredID: F8

Case: M, 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 10.

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

I'm so surprisng about just a bill can cause such a strong feeling in the narrator's mind.

I think the narrator was storming in his head and found that interesting to see what happened.

PatientID: 29

KindredID: 1

Case: M, 10Y0M, 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 10Y0M. 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: 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: 1

KindredID: 1

Case: F, 16Y0M, Ukrainian

DiseaseAssertion: Assumed VHL

FamilyInfo: Her brother (patient 2) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

CasePresentingHPOs: HP:0001901, HP:0005954, HP:0000077, HP:0001028 (polycythemia, pulmonary capillary hemangiomatosis, abnormality of the kidney, hemangioma )

CaseHPOFreeText: Patient had a hematocrit of 68%, erythropoietin level of 45 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo. She was diagnosed with polycythemia of unknown duration; at the age of 10 years, a pulmonary angioma was found and treated by a coil embolization. She continued to be polycythemic. At the age of 15 years, an abdominal computed tomography (CT) scan revealed a left renal mass, which on nephrectomy was determined to be a subcapsular hemangioma; there was no evidence of an angioma elsewhere. One year after surgery, she still remains polycythemic but has no evidence of a new or recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Y(c.376G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

gnomAD: N/A

VariantEvidence: Patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: D126Y(c.376G>T)

MultipleGeneVariants: N/A

The speaker, by giving specific male figures, mentions the inequality of gender. Men can have many wives. However, why can women marry five times? The speaker wants to break the social inequality. In modern society, this kind of resistance to established social norms can be described as social disobedience.

PatientID: 2

KindredID: 2

Case: M, 10Y6M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: de novo mutation found: his parents were said to have tested negative for the mutation (neither parent had this R167W mutation). All other family history was negative.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: this patient was described to be practically asymptomatic, with an incidental finding: Diagnosed with adrenal incidentaloma, he had intermittent abdominal pain for 6 months (beginning at age 10Y). CT scan showed a left adrenal solid tumor (3x3cm) with no calcifications; I-MIBG was normal; he underwent an adrenalectomy for this pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: brain and spinal cord MRI, ophthal-moscopy, whole body CT scan and ultrasonography of the testes, showed no abnormalities.

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: 8

KindredID: 8

Case: 10Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: isolated bilateral pheochromocytoma first presenting at 10Y

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

GroupID: 14

DiseaseAssertion: assumed VHL

GroupSize: 11

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 28.8Y +/- 19.6Y

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 11 members total were described, and phenotypic information was given for this group.

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

GroupHPOFreeText: 6 of the 11 members presented with CNS hemangioblastoma (with a mean age of 33.0Y), renal cell carcinoma in 4 members (at the mean age of 42.3Y), pancreatic cysts in 4 members (also at the mean age of 42.3Y), and a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) in 1 member at the age of onset of 10Y

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

GroupNotHPOFreeText: No patients presented with retinal capillary hemangioma or pheochromocytoma

GroupPreviousTesting: N/A

PreviouslyPublished: see more information in 29330336 (2 families of 11 people total), and 28388566 (as family #52 (9 members), and #53 (2 members)).

SupplementalData: N/A

Variant: c.464-1G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

This reminds me of when I was learning the subjects I hate, like math or science. It indeed felt hollow since I couldn't understand anything the teacher was talking about and felt very lost.

PatientID: 1

KindredID: 5

Case: F, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's mother (4) also carried this mutation and had a hemangioblastoma. The proband's aunt (5) was confirmed to have the mutation and had VHL presentations. The cousin (8) had the mutation but was asymptomatic. The grandfather (13) was inferred to have the mutation and had a hemangioblastoma. See Figure 2a for family pedigree.

CohortInfo: 20 unrelated VHL families from an ethnically diverse cohort containing both affected and unaffected individuals.

CasePresentingHPOs: HP:0010797, HP:0001732 (hemangioblastoma, abnormality of the pancreas)

CaseHPOFreeText: The patient presented with a hemangioblastoma and abnormality of the pancreas at age 10.

CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666, HP:0000077 (retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma, abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 31368132

SupplementalData: Supplementary file 1.

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 1

Case: F, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: No family history, authors indicate that the variant occurred de novo.

CasePresentingHPOs: HP:0007514; HP:0000017; HP:0004421; HP:0012594; HP:0002666; HP:0001920 (Edema of the dorsum of hands; Nocturia; Elevated systolic blood pressure; Moderate albuminuria; Pheochromocytoma; Renal artery stenosis)

CaseHPOFreeText: Patient presented with occasional high routine blood pressure at 10Y0M. She noted mild hand edema over the past days and reported recent nocturia. Physical examination appeared normal other than elevated blood pressure of 139/113 mm Hg. Urine tests showed moderate albuminuria (albumin-creatinine ratio of 50 mg/g), as well as high levels of noradrenaline and normetanephrine, suggestive of benign pheochromocytoma. Ultrasound showed normal kidney size and parenchyma, but color duplex sonography revealed increased flow rate of the left renal artery. This finding suggests renal artery stenosis. Magnetic Resonance Angiography of the kidney vessels showed a solid tumor that had cystic features. Tumor resection normalized blood pressure and pathologic examination of the removed tumor confirmed pheochromocytoma. Patient was diagnosed with secondary hypertension due to compression of renal vessels and catecholamine production by vHL-associated pheochromocytoma. Antihypertensive therapy with phenoxybenzamine as α blockade was initiated, along with subsequent expansion of the therapy with a β-blocker. Authors mention that the patient is in complete remission with no other manifestations of VHL disease and is receiving close follow-up.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G104V (c.311G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223183, https://www.ncbi.nlm.nih.gov/clinvar/variation//223183/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G104V (c.311G>T)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 7

Case: M, 17Y0M, 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 had a benign bilateral pheochromocytoma that was secreting norepinephrine at age 10. At age 17, the pheochromocytoma reoccured but this time was malignant and metastasized to the lungs.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: Yes source unknown.

SupplementalData: N/A

Variant: p.R167W (c.499C>T) *The authors of this paper have seemingly called the wrong protein change for this variant.

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: II-2

KindredID: 1

Case: F, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromoyctoma

FamilyInfo: The patient’s brother (II-1) was found to harbor the same germline mutation the patient harbored and had bilateral adrenal pheochromocytoma at 14Y. The same germline missense mutation was detected in another sister (II-4) with right adrenal pheochromocytoma and her asymptomatic daughter (III-1). The father was not available for genetic testing because he had died, apparently secondary to a hypertensive crisis. The five other family members which underwent genetic testing did not have the mutation.

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: At 10Y, the patient reported palpitations, weight loss, diaphoresis, and shooting pain attacks. Her urinary metanephrines were elevated to 12.2 mg/g creatinine. A CT of the abdomen revealed a mass in the left adrenal gland. Histology and immunohistochemistry confirmed diagnosis of left adrenal pheochromocytoma. Additional screening revealed no other tumours, so this fit the criteria of VHL type 2C.

CaseNotHPOs: HP:0002668; HP:0012090; HP:0012210 (Paraganglioma, abnormal pancreas morphology, abnormal renal morphology)

CaseNotHPOFreeText: There were no lesions in the pancreas or the kidney, there was also no suggestion that the paraganglia would also be involved. Her MRI of the brain, and her echocardiogram were both normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F(c.496G>T)

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

While most people would describe a child's eyes as "innocent" he actually described them as "cunning."

The narrator doesn't know what Sonny looks like now, which suggests that they haven't been in contact for a long time. However, the news of Sonny's arrest still affects him deeply.

I'm so interested why the narrator doesn't hate him anymore.Was it because the narrator felt pity for the man, or was there another reason why he let go of his resentment toward him so quickly?

I think it is surprising because she has already merged the woman trapped in the wallpaper with herself, and finally gets rid of her husband, but also drives herself crazy.

I feel troubling with this sentence because the narrator seems like she's used to be laughed by her husband, and even she already taken this for granted.

I find it interesting because she even needs to worry about her husband finding that she's writing something like diary. I think that she lacks autonomy in her marriage.

I find it interesting that John uses the act of closing the window to convey that the author's words was a draught.

Why does John feel satisfaction, rather than worry or heartache, when he sees his beloved suffering?

I don't understand why sprawling patterns commit something sinful.On the contrary, I think such patterns ought to symbolize something beautiful.

The girl just spoked to the boy with few words,and the boy is deeply fell in love to her. I am surprised at the charm the girl made to the boy.

The reason why I found this troubling is that I can't understand what kind of girl can made a boy so head over heels that he lost any patience with the daily serious of workof life.

I found this interesting because even though the boy did not fully know the girl,he has already seen her as a perfect,mind-affecting girl.

I find it interesting that the speaker talks directly to the Earth as if it could protect the warriors' possessions.

I find the description of the rocky cliff and gray heath interesting because it makes the dragon's surroundings seem lonely and harsh.

This suggests that his longing affects every part of his life, making it difficult for him to find peace.

Christian values often associate pagans with ignorance and evil. However, I wonder this creates unnecessary conflict between different beliefs. At the most fundamental level, I believe people should respect one another regardless of their religious beliefs.

It's interesting that I couldn't even guess the meaning of this phrase. I expect to encounter many similar difficulties when reading Old English poetry.

I find it interesting that Hrothgar believes Beowulf may have been sent by God. Beowulf’s mission is seen as more than just a personal act of bravery.

I wonder if the number twelve has a deeper symbolic meaning.

I find the contrast between the lofty hall-building and Grendel’s dark, isolated habitat interesting. It makes me wonder whether a person’s environment can influence their personality and behavior. Perhaps Grendel’s isolated habitat reflects his separation from human society and contributes to his hostile nature.

This passage makes me think about how evil can destroy a peaceful community.

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

This plot made me disgusted by the narrator's disrespectful behavior to both the blind man and his wife.

the reason why it is surprising for me is that the blind man more TVs than I do.I only have one TV in my room.

The reason why it is troubling for me is because of the very racist word.I could not stand any racist behavior even when I saw it on a article.

The reason why it is interesting for me is that the fact the blind don't smoke because they can't see the smoke they exhaled really made me laugh for a while

After the man dropped his bias,he felt something was gone.His spirit was no longer trapped in an invisible building, but became free.

The narrator had bias that he didn't think the blind man can feel his wife's feeling without the eye.But empathy isn't just about sight.

https://thecarrtell.blog/booklist/

5/10/1995

10

Gemini成为Google历史上增长最快的产品，月活10亿——超越Gmail、YouTube、Search达到这个里程碑的速度。这验证了AI助手不是利基产品，而是主流基础设施。现在的竞争问题变成：谁能在10亿用户规模上保持质量差异化？

全球50,000台扫描仪、每月10亿次全身扫描——这个数字大到需要放进上下文才能理解。目前全球MRI机器大约有5-6万台，那是几十年全球性基础设施建设的积累。Midjourney Medical声称在6年内复制这个规模。更野心勃勃的是「每月10亿次扫描」——这意味着每台机器每月要完成2万次扫描，即每天650次、每分钟不间断运转。这些数字要么意味着真正的技术突破（60秒/次加上高通量自动化），要么是为了叙事效果的数量级夸张。

via u/BlindAssassin111 at https://www.reddit.com/r/typewriters/comments/1u19nbi/1960_optima_super/

The Royal 10 QX (aka Quiet Model) (1921-1923) has a special mechanism in the segment which allows the slugs to hit the platen when struck, but pressing the keys slowly doesn't allow them to reach.

Via commentary by Brian Decker, Ted Muk, and James Grooms at https://typewriterdatabase.com/1927-royal-10.16643.typewriter

Thermal Typewriter Comparison<br /> by [[Joe Van Cleave]]

Ranked:<br /> 1. Sharp PA-1050<br /> 2. Brother EP-43<br /> 3. Brother EP-20 v 4. Casiowriter CW-10<br /> 5. Canon Typestar 4<br /> 6. Canon Typestar 5

https://www.facebook.com/groups/705152958470148/posts/1264728369179268/

Custom gothic typeface on a Royal 10 made for supply/hardware settings. Uppercase is primarily fractions and abbreviations including: Dz, Gr, Bx, Bl, lb, In, Ft, Pr, Cs, Pc, Yd, and GL.

Fractions include odd numbers for the halfs, thirds, fourths, sixths, eighths, twelfths, and sixteenths,

10-20 倍的生产力提升——如果这个数字属实，这是人类历史上工具对知识工作者单项生产力的最大提升，没有之一。印刷术提升了知识传播效率，但没有提升单个作者的写作速度 10-20 倍。汽车让人移动速度提升了约 10 倍。AI 编程工具在三年内实现了历史上极少数工具曾经达到的生产力倍数——而且只针对最顶尖的工程师。

Venoactive drugs (diosmin, hesperidin, horse chestnut seed extract) may be considered as adjuncts to compression for symptomatic relief in countries where available

Endovenous Thermal Ablation (RFA/EVLA)

Relative contraindications include inappropriate vein size, with veins <2 mm and >15 mm representing potential contraindications for RFA specifically. [1] A history of superficial thrombophlebitis resulting in a partially obstructed saphenous vein may preclude thermal ablation. [1] Significant tortuosity of the GSV on duplex examination can make catheter delivery difficult.

Aortic dissection typically presents acutely with sudden, severe tearing chest or back pain, often described as lancinating in quality. [5-6] Approximately 50% of patients with thoracic aortic aneurysm may progress to dissection without timely intervention. [5] In contrast, thoracic aortic aneurysm is usually asymptomatic and discovered incidentally during physical examination or imaging for other indications. [5]

elective surgical repair is suggested at 5.5 cm in patients without underlying connective tissue disorders, with earlier intervention at 4.5-5.0 cm in patients with connective tissue disorders or bicuspid aortic valve

https://youtu.be/4-8adc39DV0?si=Upi9PjBrYFiE_5kn&t=54

Misery (Columbia Pictures, 1990)<br /> clip when Paul attacks Annie

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.

DOI: 10.7554/eLife.106720

Resource: None

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-230214-10

What is this?

This is surprising because it treats speech as a cost instead of a connection. It turns silence into a form of discipline that shapes the whole family.

This is interesting because it shows identity as a messy mix, not a clean category. The question forces you to notice how culture and personal history can blur into each other.

The sentence is troubling because it turns violence into a close physical detail. It makes the threat feel intimate and unavoidable inside the home. The image also suggests that cruelty is being displayed on purpose rather than hidden.

https://www.facebook.com/groups/TypewriterCollectors/posts/10163290131069678/

https://en.wikipedia.org/wiki/Charles_Hamilton_(writer)

South Burlington

Initiatives threshold 10%

https://www.reddit.com/r/typewriters/comments/1qowfn2/mulder_is_a_fan/

X-Files (Fox), Season 2, Episode 4<br /> A poster for a Royal Ten appears on a wall behind Mulder.

https://sophsun1.tumblr.com/post/805029439375310848/misery-1990-dir-rob-reiner

for - comparison - hunter gatherer vs agricultural - energetically contained vs energetically expansionary - stats - hunter -gatherer humans - population before agriculture - 6 to 10 million people.

for - genocide - preceded by 10 preliminary stages - 1. classification - 2. symbolization - 3. discrmination - 4. dehumanization - 5. organization - 6. polarization - 7. preparation - 8. persecution - 9. extermination - 10. denial

for - inequality - advocate for - cap wealth at 10 million USD

for - stats - elites - top 10% - responsible for 50% of consumer spending

for - neuroscience - 10 tests - LinkedIn post - Beau Lotto - 10 tests - neuroscience - to - Lab of Misfits - 10 tests - Lab of Misfits - neuroscience - Beau Lotto

for - Lab of Misfits - neuroscience - Beau Lotto - from - Linkedin post - Beau Lotto - 10 tests - https://hyp.is/7YqrerxxEfCuEIeI8IcHTg/www.linkedin.com/posts/beau-lotto_who-am-i-humans-have-probably-been-asking-activity-7232008275641163779--zxp/?rcm=ACoAACc5MHMBii80wYJJmFqll3Aw-nvAjvI52uI

It is troubling that Montresor shows no hesitation or guilt while listening to Fortunato’s cries. His enjoyment of the sound of chains reveals his cruelty and the disturbing pleasure he takes in revenge.

It is surprising that Fortunato suddenly regains his awareness, but it is already too late for him to escape. Montresor’s calm reaction to his desperate struggle is unexpected and chilling.

This motto foreshadows Montresor’s plan for revenge. It warns that anyone who offends him will face punishment.

It’s interesting how he begins so calmly, just describing a painting — but there’s already something unsettling underneath. It makes me curious about what really happened to the Duchess.

I was shocked by how easily he admits giving “commands”, as if ordering his wife’s death was just another act of pride. He sounds more offended by his wife’s kindness.

The author's words appear calm, but I feel something terrible happened, like he ended his wife’s life without remorse.

I used to think that the job of college advisors was only to help with class schedules, but now I see that they also give emotional support and guidance when students face problems. It’s interesting to know that building a relationship with an advisor can really make a big difference in college life.

This situation shows how easily anxiety can keep someone from connecting with others. It’s sad that John feels the need to hide behind his phone instead of giving himself a chance to meet new people. It reminds me how difficult social situations can be when fear takes over, and how important it is to slowly build confidence to open up.

When we take care of ourselves, we have more energy and positivity to share with others. It made me realize that loving yourself is the first step to loving others. I used to think taking care of myself was less important than caring for others, but now I see how closely they are connected.

this represents the conscious effort to go beyond the surface stories 'myths' and confront the deeper, often hidden realities 'the wreck'

I was so suprised that the author uses ladder to represnts the fear of his alone.

I love the author writes about the stress that the author can't support about it.

What is the mask is about? Is a phase or a another thing?

As the author stroke his beam of his lamp on the flank, what he was doing can be looking back the wounds and emotions he had. And it's something that comes and never goes, unlike fish or weed, which doesn't leave lasting impact to our brain.

The speaker finally reached the wreck and become part of it. Calling herself both the mermaid and the merman could suggest that she feels connected to different sides of human experience, not limited by gender.

This part might mean that the speaker’s goal is to truly explore and understand the wreck, not just read about it. The “words” could represent stories or explanations that guide her, like maps, but she still needs to see the truth for herself.

This might describe how the she feels awkward and alone while going deeper into the sea. The image of crawling “like an insect” could suggest weakness or discomfort.

I see nothing in common at this point, and cannot associate the two lines.

I think it’s interesting how the ordinary diving equipment becomes symbolic, like “black rubber body armor” and “awkward mask,” suggesting emotional or psychological protection.

I think when she says it's easy to forget what she came for, it;s because there's so much to take in down there ; not just the wounds and broken things, but also strange , hauntingly beautiful details that make you want to stay and wander.Tat's why there seem to be people who have 'always lived here' - they've settles among the ruins, maybe trapped by it or maybe finding a kind of comfort in it.

I think this is powerful because it shows that we are all part of this search. Even if our names weren't written in the old stories, we can still go down there and see the wreck for ourselves. I think the wreck here might be our traumas or things we try to forgetting. this line is really deep

I love how she describes the wreck so vividly that we can picture it. it makes me think of the dark times in our own lives when we wanted to reach the sunlight so badly. some things we believed would last forever ended up drifting into the 'ocean of lost memories' I especially like the part about the ribs, it feels like those old hurts we try to ignore, but every now and then they poke us again. we can't really erase them ;we just learn to move around them, like tentative haunters of our own past.

the ladder is a symbol of a way into depths of history/memory, but here she wrote 'we who have used it' implying that not everybody chooses descend..Only the ones who choose to climb down can really start to face themselves and hidden truths.

unlike heroic male explorers, the speaker dives alone leads to feminist emphasis on personal, solitary quest

From this passage we can see the narrator keeps looking after his brother for fear of him being trapped by drugs again ;the theme of the obligation toward brotherly love.

It’s ironic that Sonny got arrested, while the drifter was fine.

It seems like he didn’t know exactly what happened to Sonny.

I’m curious about why the man would do that. Was he kicking Sonny when he’s down?

I thought Sonny was destroying himself because he wanted to die, but this line shows the opposite. It’s shocking that even through self-destruction, Sonny is still fighting to live.

It’s troubling because it reminds us that suffering never disappears; people keep reliving pain through their own stories. The line suggests a cycle that’s hard to break.

It’s surprising how the narrator realizes that Sonny’s music expresses not only his own pain but the shared suffering of others. This shows a moment of understanding and connection between the brothers.

Interesting because the narrator’s sudden hatred isn’t really about the boy but his own fear and guilt about Sonny, showing how deeply conflicted he feels inside.

When Creole says that ' blues weren't anything new' ,is it because the music they play all derived from their past feelings and emotions? or is it telling us that sonny's expressing his life? ( But I think both are things he wanted to tell us)

the narrator's reaction to Sonny's music shows howdleeply it moves him. I think it's also a turning point where he finally begins to understand Sonny.

It shows how trapped he felt by his environment. Harlem represents pain , poverty , and a cycle he wants to escape. This highlights a main theme of the story - how hard it is to break free from suffering.

It's clear that Black people have a really deep connection with music, and jazz is a big part of Black culture. This idea plays a significant role in Sonny's Blues, highlights how music becomes a way to deal with pain and as a form of expression.

The narrator's mother, by charging him watching over Sonny, is asking him to serve as his brother's keeper. Another passage about the obligation toward brotherly love.

'Sunday dinner' and 'church' are strongly associate with the Black culture in the US, representing a traditional rooted in the resilience of African Americans during and after slavery.

The speaker, as someone who has tried heroin before , must have a remarkably stable mind to avoid being controlled by the drug. I strongly agree with the line,'He wants to live. Don't nobody want to die, ever.' It reveals the underlying reason why many people become addicted; they long to escape a reality that they cannot bare living.

I think ' a teacher ' might refer to the narrator himself; otherwise , why is it every ' now and again'?

I don't think that only boys at that age would be on drugs. Girls might tool. Also, I quite like the way that the narrator describes addictive products as 'darkness' and something they 'dreamed' - it's truly a kind of lust.

How to make the best possible translation of a book? | Derek Sivers<br /> by [[Derek Sivers]]<br /> accessed on 2025-10-15T19:19:44

Lanier, Jaron. 2006. “Digital Maoism: The Hazards of the New Online Collectivism.” Edge.org. https://www.edge.org/conversation/jaron_lanier-digital-maoism-the-hazards-of-the-new-online-collectivism (October 11, 2025).

I think the two roads symbolize the choice we all face in life - one may be destiny and the other fate, but no matter which we choose , it leads us to a certain way of living and becoming ourselves.

Her mother's garden symbolizes suppressed female creativity-beauty and art growing from struggle, like magic.

Society once saw creative women as "mad", but their so-called madness is actually passion, vision and art.

Nebula<br /> accessed on 2025-10-04T09:27:37

Nebula is smart, thoughtful videos, podcasts, and classes from your favorite creators.

It’s troubling that the narrator thought, I believe the woman didn’t care about whether the blind man knew what she looked like. She just knew her husband sincerely loved her.

I am surprised that the woman would allow the blind man to touch her face since it’s not a common request.

It’s interesting that the narrator put himself on the blind man’s wife and tried to imagine her life.

It’s quite scary if the pattern of my wall paper is like a woman stooping and creeping.

I am surprised that a how come the wife should pretend she was fine but not in front of her physician husband.

for - youtube - Google Talks - Humans need not apply - Jerry Kaplan - 10 years after the book "Humans need not apply - the AI 2027 project - https://hyp.is/kWXQ0n3cEfCIUz_j42HHiA/www.youtube.com/watch?v=1UufaK3pQMg

https://www.reddit.com/r/typewriters/comments/1mqcu0f/erika_typewriters_i_am_looking_to_potentially_get/<br /> via LeSwiss1886

for - Jeffrey Epstein victims - under 10 years of age

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

https://www.facebook.com/groups/705152958470148/posts/1013993200919454/

Royal X typewriter in Tintin in America

Type Shop, Ep. 3: How to remove and install the carriage on a Royal Standard Desktop Typewriter by [[Typewriter Chicago]]

Ken Mandls JAMIA article highlying the CURES ACT rules on interop

Zur Haltung des neuen Papsts zur Klimakrise. Er hat davon gesprochen, dass die Beherrschung der Natur durch den Menschen nicht auf Tyrannei, sondern auf Reziprozität beruhen müsse. https://reporterre.net/Sur-le-climat-le-pape-Leon-XIV-appelle-a-passer-des-mots-a-l-action