PatientID: 4

KindredID: 4

Case: F, 51Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s mother had duodenal carcinoid and her second son had pheochromocytoma.

CasePresentingHPOs: (HP:0002666; HP:0030405; HP:0009713 (Pheochromocytoma; pancreatic endocrine tumor; spinal hemangioblastoma)

CaseHPOFreeText: Patient presented with right pheochromocytoma at 23Y0M and left pheocromoctytoma at 32Y0M, pancreatic endocrine tumor at 32Y0M, and spinal cord hemangioblastoma was suspected.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: BRCA1, BRCA2, TP53, STK11, MLH1, MLH2, MLH6, PMS2, APC, MEN1, RET, NTRK1, PTEN, RB1, SDHD, SDHAF2, SDHC, SDHB, TSC1, TSC2 and WT1 (table 2)

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: Germline, DHD, c.331G>A (p.Val111Ile); Germline, WT1, c.1249+7G>C (p.?)

PatientID: 5

KindredID: 3

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: A family pedigree is provided in figure 1. Both the son and daughter of patient 5 were found to have the same mutation. Neither the 10-year-old daughter, nor the 7-year-old son had RCHs or any other tumors.

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0009713; HP:0000541 (Cerebellar hemangioblastoma; Retinal capillary hemangioma; Spinal hemangioblastoma; Retinal detachment)

CaseHPOFreeText: Patient had an ophthalmic emergency service in 2010 at age 32Y0M. His visual acuity was 20/32 in the right eye, but fundoscopic examination revealed three peripheral RCHs with retinal detachment. Moreover, two small retinal lesions were detected in the left eye, yet the visual acuity of this eye was 20/20. The patient underwent retinal surgery in the left eye and lesions of both eyes were treated with multiple laser sessions. CNS imaging revealed multiple cerebellar and spinal hemangioblastomas. In 2012, cataract surgery was performed in the right eye. In 2019, visual acuity was 20/20 in both eyes and all the RCHs regressed.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: 32Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Family history unremarkable; Patient was confirmed to have a de novo mutation.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0030424 (hemangioblastoma; retinal capillary hemangioma; renal cyst; epididymal cyst)

CaseHPOFreeText: Aged 32Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. Retinal hemangioblastomas and CNS hemangioblastomas diagnosed at 32Y, renal cysts were also diagnosed at 32Y, while epididymal cysts were diagnosed first at 23Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497423672 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497423672

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s niece, age 27, presented with two right renal masses and several pancreatic cysts at 22Y. The patient’s brother, age 45, presented with right ccRCC and pancreatic cysts. Both the patient’s daughter and brother were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0006770 (Clear cell renal cell carcinoma)

CaseHPOFreeText: The patient presented with unilateral ccRCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s daughter, age 27, presented with two right renal masses and several pancreatic cysts at 22Y. The patient’s brother, age 38, presented with unilateral ccRCC. Both the patient’s daughter and brother were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0006770; HP:0001737 (Clear cell renal cell carcinoma, pancreatic cysts)

CaseHPOFreeText: The patient presented with right ccRCC and pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: None(c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 13

Case: M, 44Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Son and brother presented with the same VHL variant. Son is asymptomatic. Brother presented with CNS hemangioblastoma at 29Y, retinal hemangioblastoma at 52Y, bilateral RCC at 43Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 43Y and bilateral renal cysts at 43Y. Nephew presented with CNS hemangioblastoma at 22Y, retinal hemangioblastoma at 18Y, bilateral RCC at 29Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 18Y but was not genetically confirmed.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0001732; HP:0010797; HP:0005584; HP:0009711 (Abnormality of the pancreas, Hemangioblastoma, Renal cell carcinoma, Retinal capillary hemangioma)

CaseHPOFreeText: CNS hemangioblastoma at 32Y, retinal hemangioblastoma at 44Y, bilateral RCC at 44Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 41Y. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0000107; HP:0002666 (Renal cyst, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: III:3

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her paternal grandfather (I:1) had been diagnosed with an adrenal tumor and hypertension in his 40s. In addition, four other relatives developed unilateral PHEOs: her father (II:1) at age 73, her 34-year-old brother (III:2), her paternal aunt in her 40s (II:4), and the aunt’s 12-year-old son (III:7). Subsequently, the son of III.7 (IV:3) was also diagnosed with PHEOs at 23 years of age. All affected individuals underwent adrenalectomy and remain asymptomatic, 1 to 30 years after surgery. In addition, a renal cyst was detected in individual III.2 at the time of the PHEO diagnosis, whereas II.1 developed multiple spinal cord hemangioblastomas after the adrenal tumor resection. No RCCs were diagnosed. Other declared diseases in this family are: thyroid nodule and bladder carcinoma but the presenting patient is unclear.

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with a normetanephrine-secreting, 5-cm right PHEO with no other clinical features of VHL disease.

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

Josh Brolin has one of Cormac McCarthy's Olivetti Lettera 32 typewriters.

PatientID: 3

KindredID: C

Case: F, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Hemangioblastoma

FamilyInfo: Positive: The patient’s sister, one of two brothers, and mother each had the same germline mutation, although without any manifestations. As such, her family history was negative for kidney cancer, hemangioblastoma, or other features of VHL. See Fig. 3.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: In 2013, at 32Y, patient presented with a hemangioblastoma in her cerebellar region.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No other VHL- related tumors are present in this patient.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.P81S (c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: Immunohistochemistry was positive for Inhibin, and negative for RCC, GFAP, and OLIG2.

MutationType: missense_variant; transition

CivicName: P81S (c.241C>T)

MultipleGeneVariants: Somatic, VHL, c.188_188T>TG (p.Leu63fs*4)

PatientID: 11

KindredID: 1112

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (Pancreatic endocrine tumor)

CaseHPOFreeText: The patient presented with one pathologic pancreatic neuroendocrine tumour at age 32. The tumour had metastasized.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10(c.477del)

LegacyVariant:p.E160Sfs*10(c.688delA)

CaseProblemVariantFreeText: N/A

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName:E160fs (c.477del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo:

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82G (c.244C>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her two sons and her father had the same VHL mutation.

CohortInfo:Three patients with endolymphatic sac tumors were studied.

CasePresentingHPOs: HP:0001737, HP:0002666, HP:0030393, HP:0009713 (pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, spinal hemangioblastoma)

CaseHPOFreeText: She presented with pancreatic cysts and pheochromocytoma at age 32. She experienced headache and dizziness and a temporal bone mass consistent with an ELS tumor was found on brain MR imaging. A preoperative audiogram showed no hearing function and she underwent a left transcochlear approach and resection of the tumor. The pathological diagnosis was consistent with an ELS tumor. She was later found to have a spinal hemangioblastoma that was resected and included in this study.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: The paper describes the mutation as "C-to-A transversion at position −1 on the exon 3 splice acceptor sequence in the VHL gene"

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: P1

KindredID: 1

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s father, age 45, presented with right ccRCC and pancreatic cysts. The patient’s uncle, age 38, presented with unilateral ccRCC. Both the patient’s father and uncle were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0009726; HP:0001737 (Renal neoplasm, pancreatic cysts)

CaseHPOFreeText: The patient presented with two right renal masses and several pancreatic cysts at 22Y.

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

CaseNotHPOFreeText: Full VHL phenotyping with brain and spine MRI, abdominal CT, biochemical examination for pheochromocytoma, and ophthalmologic assessments did not reveal any additional VHL manifestations.

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

PatientID: II:1 (proband)

KindredID: 1

Case: M, 42Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband presented with VHL Type 2B. Sister presented with features of VHL Type 2A including cerebral hemangioblastomas, a right adrenal nodule, multiple cysts in the pancreas, multiple cysts in the liver, two brain lesions. The younger brother and their deceased father had hemangioblastomas in the central nervous system and ocular diseases, respectively. Despite having no information of detailed clinical data, it is reasonable to assume that they had VHL diseases. The father was also blind, but the reasons are unknown. The mother had no history of disease. Pedigree: see Figure 3.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0006770; HP:0030421 (Hemangioblastoma, Renal cell carcinoma, Clear cell renal cell carcinoma, Epididymal neoplasm)

CaseHPOFreeText: Ten years prior (at the age of 32), the patient received gamma knife treatment for cerebral hemangioblastomas. Magnetic resonance (MR) of the abdomen showed multiple solid lesions in the bilateral kidneys, multilocular renal cysts, a right adrenal nodule, multiple cysts and a solid lesion in the pancreas, and multiple cysts in the liver. The pathological manifestations confirmed ccRCC concurrent with simple renal cysts. The left side kidney showed multilocular cysts lined by clear cells. Pathology confirmed the presence of clusters of clear cells. mcRCC was confirmed pathologically. Scrotum MR suspected a malignant tumor on the right side epididymis.

CaseNotHPOs: HP:0000822; HP:0100631 (Hypertension, Neoplasm of the adrenal gland)

CaseNotHPOFreeText: No history of hypertension disease. Common tumor markers such as AFP, CEA, and PSA were normal. Special tests for adrenal lesions included plasma cortisol, renin angiotensin aldosterone, and urinary VMA, which were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA020288, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA020288

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

VariantEvidence: Direct sequencing of DNA strands revealed 2 recurrent mutations of c.256C > T (p.P86S) and c.340 + 5G > C. Haplotype construction displayed that the c.256C > T (p.P86S) mutation in cis with c.340 + 5G > C were located on the disease haplotype. Bioinformatics analysis revealed that this mutation might severely destabilize the hydrophobic core of pVHL and cause VHL manifestations. This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: P86S (c.256C>T) and Splice Region (c.340+5G>C)

MultipleGeneVariants: Germline, VHL, c.256C>T (p.Pro86Ser)

PatientID: 142

KindredID: 52

Case: F, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

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

CaseHPOFreeText: The proband's sister 1 (patient 142) had a CNS hemangioblastoma at 31, and multiple pancreatic cysts/tumors and renal cell carcinoma at 36.

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

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: 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

PatientID: 98

KindredID: 33

Case: M, 43Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 97) presented with a CNS hemangioblastoma at 37, retinal angioma at 20, and renal cell carcinoma and multiple pancreatic cysts/tumors at age 29. Their brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseHPOFreeText: The proband's brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.P97Afs*35 (c.287_288insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420510, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.287_288insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P97Afs*35 (c.287_288insA)

MultipleGeneVariants: N/A

PatientID: 217

KindredID: 81

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0000790, HP:0009711, HP:0000107, HP:0009713, HP:0010797, HP:0006770 (hematuria, retinal capillary hemangioma, renal cyst, spinal hemangioblastoma, hemangioblastoma, clear cell renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R120*(c.358A>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753732 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.358A%3ET

gnomAD: N/A

VariantEvidence: All tumor regions also displayed 3p LOH.

MutationType: stop_gained

CivicName: R120*(c.358A>T)

MultipleGeneVariants: Somatic, VHL, not described

PatientID: 1 (case)

KindredID: 1

Case: F, 33Y0M, Ethnicity Unknown

DiseaseAssertion: endolymphatic sac tumor

FamilyInfo: Her mother and elder sister had history of resection of cerebellar hemangioblastomas, although no genetic testing was done for them.

CasePresentingHPOs: HP:0030393 (endolymphatic sac tumor)

CaseHPOFreeText: Woman had progressive hearing disturbance, vertigo, and headache since 32Y. MRI revealed a 4.5 × 3.8 × 3.5-cm mass was detected in the right cerebellopontine angle, destroying the cerebellum. CT with a bone window mode demonstrated extensive destruction of the petrous bone and middle ear structures (endolymphatic sac tumor). The patient underwent craniotomy for a complete removal of the tumor. To date of publication, the patient remains well, with no evidence of recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

LegacyVariant: 553 + 1G→A, designated as IVS1 + 1G→A mutation

CaseProblemVariantFreeText: N/A

ClinVarID: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: N/A

gnomAD: N/A

VariantEvidence: No LOH was found in this sample

MutationType: splice_site_variant

CivicName: Splice site (c.340+1G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 40Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: None - The DNA analysis of close relatives did not show affected subjects

CasePresentingHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma; retinal capillary hemangioblastoma)

CaseHPOFreeText: also had high intercranial pressure; developed a retinal hemangioblastoma 4 years after diagnosis (diagnosis at 32Y0M; rHAB at 36Y0M)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86L (c.257C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history. All 7 of his other family members (his parents, sister, son, sister’s son, brother, and brother’s son) were sequenced and no mutation were found. Additionally, all were healthy members. Suggestive of de novo due to no abnormal changes in the VHL gene of either parent.

CasePresentingHPOs: HP:0010797; HP:0009713; HP:0006880; HP:0009726 (hemangioblastoma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm)

CaseHPOFreeText: At 32Y this patient presented with progressive back and neck pain and numbness. Patient developed multiple CNS hemangioblastomas (multiple lesions in the cerebellum, brain stem, and spinal cord). Subsequent evaluation of the abdomen revealed a solid kidney tumor (visceral tumor).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTCT)

MultipleGeneVariants: N/A

PatientID: II:3 (proband 4)

KindredID: 4

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s mother (I:1) was found with the same mutation and RCC at 63Y. The proband’s brother (II:1) died before diagnosis; thus no DNA sample available. He presented with hemangioblastoma at 19Y

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

CaseHPOFreeText: patient had hemangioblastoma at 22Y and retinal capillary hemangioma at 32Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: 3 (Father)

KindredID: 10

Case: M, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: HGB-19

KindredID: 4

Case: Sex Unknown, 44Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

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

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 32. The patient had a spinal cord hemangioblastoma at age 40.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114V(c.341G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753604 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.341G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114V (c.341G>T)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 11

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: There was said to be, at the time, no affected relatives

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

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0006476; HP:0006880; HP:0009711; HP:0000618; HP:0010797 (adrenal pheochorocytoma, paraganglioma, abnormality of the pancreatic islet cells, cerebellar hemangioblastoma, retinal capillary hemangioblastoma, blindness, hemangioblastoma)

CaseHPOFreeText: At 8Y, (in 1978), she was operated for a right pheochromocytoma; at age 13 for a contralateral pheochromocytoma; at age 15, for a 4-cm mass at the neck was diagnosed by selective arteriography as a carotid paraganglioma. The patient was then operated twice for cerebellar hemangioblastoma at age 22, leading to the diagnosis of VHL disease. At age 27, the patient was operated again for a retrocaval pheochromocytoma and for islet cell tumors. The patient was also repeatedly treated for bilateral retinal hemangioblastomas leading to blindness at age 32. At age 36, again a pheochromocytoma was removed

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.T157I

CaseProblemVariantFreeText: The publication only provides the p., the mutation was able to be deduced to p.T157I (c.470C>T)

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: N/A

PatientID: B1

KindredID: 1

Case: Sex Unknown, 28Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: No testing

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.582_589delGACACAC

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: T124Mfs*33(c.369_375del)

MultipleGeneVariants: N/A

https://www.facebook.com/groups/705152958470148/posts/1253571376961634

https://www.facebook.com/groups/705152958470148/posts/1224514289867343/

Season 4, episode 4 “Happy Trails”

Typewriter Profile: Comparing the Olivetti Lettera 22, Lettera 32, and Studio 44<br /> by [[Damon Di Marco]] of CreateX3.com on YouTube<br /> accessed on 2026-01-19T11:32:11

Marcello Nizzoli designed the Olivetti Lettera 22, an ultra-portable, and the standard Lexicon 80. He used the automotive idea of press-forming steel to the Olivetti line.

In 1959, the Illinois Institute of Technology chose the Olivetti Lettera 22 as the best designed product of the last 100 years. It also won the Compasso D'Oro Award in 1954.

1963 Lettera 32 introduced<br /> Square keys

1965 Olivetti Studio 44 introduced<br /> Between the standard and the portable<br /> Comes with a case, but is heavier than many portables

Prefer original spools with spool nuts.

https://mrmrsvintagetypewriters.com/collections/typewriter-accessories-parts/products/one-spool-nut-olivetti-typewriter-lettera-22-32-44-studio-45-dora-dl-underwood-315-screw-holder

Find out more! Who was Andrei Dashkov? What did he do (if anything) in his work with the United States?

Cite your source(s)!

Me starts thinking about cornering the market in Lettera 32s and 3D printing Valentine cases to put onto them...

1:27:32 A Community Bill of Rights

Cormac McCarthy's Typewriter Brings $254,500 at Auction by [[Randy Kennedy]] on 2009-12-04

Designer Marcelo Nizzoli designed the Lettera 22, 32, and Studio 44.

I learned that science and cooking is always connected. Even if we don't think about it in every day life like when water evaporates or freezes it is chemistry. But what I found most interesting that I learned is how water immobilization works, or to put it more simply the science behind Jell-O. When you add gelatin to water it traps the water molecules in place which creates the sort of liquid and solid hybrid we find with Jell-O.

In dem bisher umfassendsten Klimaprozess klagen 6 portugiesische Kinder und junge Menschen vor dem Europäischen Menschenrechts-Gerichtshof gegen 32 Nationen, um sie zu einer schnellen Senkung ihrer Emissionen zu zwingen. Sie haben inzwischen erreicht, dass ein Hearing vor der Grand Jury des Gerichtshofs stattfand. https://www.theguardian.com/environment/2023/sep/14/young-people-to-take-32-european-countries-to-court-over-climate-policies

In the West Semitic pantheon of gods, El was the father of Dagon who was in turn the father of Baal. El Elyon is mentioned in Deuteronomy 32:8-9 and his name is a root word of the endonym Israel.

DOI: 10.1016/j.devcel.2021.07.021

Resource: (ZFIN Cat# ZDB-ALT-111118-32,RRID:ZFIN_ZDB-ALT-111118-32)

Curator: @Naa003

SciCrunch record: RRID:ZFIN_ZDB-ALT-111118-32

What is this?

AssayResult: 4.5

AssayResultAssertion: Normal

StandardErrorMean: 0.16

HGVS: NM_024675.3:c.2612A>G p.(Asp871Gly)

AssayResult: 34

AssayResultAssertion: Abnormal

PValue: < 0.0001

AssayResult: -34

AssayResultAssertion: Abnormal

PValue: < 0.0001

AssayResult: 64.45

AssayResultAssertion: Abnormal

PValue: < 0.0001

Comment: Exact values reported in Table S3.

HGVS: NM_024675.3:c.3418T>G p.(Trp1140Gly)

AssayResult: 14.78

AssayResultAssertion: Abnormal

ReplicateCount: 2

StandardErrorMean: 9.34

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

AssayResult: 7.63

AssayResultAssertion: Abnormal

ReplicateCount: 2

StandardDeviation: 0.51

StandardErrorMean: 0.36

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

HGVS: NM_024675.3:c.2831T>A p.(I944N)

AssayResult: 29.8

AssayResultAssertion: Abnormal

ReplicateCount: 13

StandardErrorMean: 5.7

Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

HGVS: NM_198056.2:c.2780A>G p.(Asn927Ser)

AssayResult: 51

AssayResultAssertion: Normal

Comment: See Table S2 for details

AssayResult: 4.9

AssayResultAssertion: Abnormal

Comment: See Table S2 for details

HGVS: NM_000546.5:c.673-2A>G p.?

In questo articoletto fake dall'inizio alla fine, l'autrice scrive delle cose abominevoli..Ma dove sta scritto che i vaccini sono imposti dall'articolo 32 della Costituzione Italiana?

L'art. 32 testualmente recita: "...Nessuno può essere obbligato a un determinato trattamento sanitario se non per disposizione di legge. La legge non può in nessun caso violare i limiti imposti dal rispetto della persona umana..."

In the first paragraph there is an evocation of the triad of First Principles: Mythos, Typos, Logos (GOD, Place, Word) The Mythic moves and opens up spaces. From that spatial existence known by/as Persons and Places come Things - works/words, art/artifacts, etc. Myths open spaces and rational accounts limit them. These are two parts of one eternal process. Mythos creates space through its mysterious movements. Then within the spatial existence opened by Mythos we have a spatial/special relationship between Peope & Place which always begins to generate Names and other Words. From there the Spirit continues to flow through linguistic channels (Logos) and finally deposited back into the realm of Myth to begin again. [If at any point in this process there is a failure to complete and continue the cycle then what comes about is "vain imaginings" as opposed to the reimagining encouraged on this site. This will be a major theme throughout the BOM.]

Limitation - One man's account, one man's knowledge. The content itself is a product of the quality of experience and great knowledge accumulated through the person of Nephi (who is likely a higher dimensional type for millions of others who share to some degree in the experience of "favor" and "goodness" on any and all planes). The accuracy of recording relies on the "Learning of the Jews" (Scientific Judgements and Measurements of Truth) and the "Language of the Egyptians" (Science of Expression of Truth through Active Arts).<br> Compare Alma 32:26-43

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

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

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

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

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

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

What this means is that the government has really not desire about the people and they don't care what is being said at all in that matter.

Even though the DR is making great strides to be more modern, they still find difficulties in handling human rights

It is nice to hear more about the LGBT's progression of being recognised in other parts of the world other than the U.S.

how they can not implement a national human rights plan. they should have one

for me is a big step for changing the world. seeing this make me happy that people are coming out and doing whats they want

I couldn't imagine going through this. Both my parents are European immigrants and I am an American citizen, and I can't imagine being told that I can no longer be an American citizen just because my parents aren't.

All humans have basic rights, and by separating families you are violating their rights People of different nationalities are feeling in violation of their rights as they fear deportation and separation of their families

We have this type of issue now with the mass population with illegal immigrants that Trump promised to deport. When we hear about it from other countries, we think it is cruel but we voted for a president who plans on doing the same thing in our country.

I cannot imagine having my citizenship taken away from me after fleeing from a country where it had a lot of violence and dictatorship. I can safely say that it is as if taking my safety away from me and throwing me out back to the wolves.

This is 32 pages. How to highlight /