GroupID: 13

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 39.0Y +/- 13.1Y

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

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts)

GroupHPOFreeText: 5 of the 7 members presented with CNS hemangioblastoma (with a mean age of 34.2Y), retinal capillary hemangioma in 1 member at 26Y, renal cell carcinoma in 3 members (at the mean age of 36.7Y), pancreatic cysts in 2 members (at the ages of 32 and 38Y)

GroupNotHPOs: HP:0002666; HP:0009715 (pheochromocytoma, papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No patients presented with pheochromocytoma or a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament)

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336; 28388566

SupplementalData: N/A

Variant: p.I151S (c.452T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223215 https://www.ncbi.nlm.nih.gov/clinvar/variation/223215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: I151S (c.452T>G)

MultipleGeneVariants: N/A

PatientID: 1695

KindredID: 1695

Case: Sex Unknown, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 44 patients with renal cell carcinoma who had known industrial exposure to trichloroethylene (TRI).

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The patient had TRI exposure at age 27 and was diagnosed with renal cell carcinoma at age 38.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V(c.562C>G)

LegacyVariant: p.L188V(c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/?new_evidence=false

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: The patient had LOH.

MutationType: missense_variant;transversion

CivicName: C162Y(c.486C>G) and L188V(c.562C>G) and P81S(c.241C>T) and F119L(c.357C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser), , Somatic, VHL, c.357C>G (p.Phe119Leu), Somatic, VHL, c.486C>G (Cys162Trp)

PatientID: 1695

KindredID: 1695

Case: Sex Unknown, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 44 patients with renal cell carcinoma who had known industrial exposure to trichloroethylene (TRI).

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The patient had TRI exposure at age 27 and was diagnosed with renal cell carcinoma at age 38.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L(c.357C>G)

LegacyVariant: p.F119L(c.570C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/?new_evidence=false

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had LOH.

MutationType: missense_variant;transversion

CivicName: C162Y(c.486C>G) and L188V(c.562C>G) and P81S(c.241C>T) and F119L(c.357C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser), Somatic, VHL, c.486C>G (Cys162Trp) Somatic, VHL, c.562C>G (Leu188Val)

GroupID/ KindredID: 26

PatientID: II

Case: 40Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 26 consisted of 2 members; One other member (37Y) was diagnosed with a single cerebellar HAB at 32Y

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

CaseHPOFreeText: Patient was diagnosed with a single spinal HAB, and a single cerebellar HAB at 38Y

CaseNotHPOs: HP:0009711; HP:0005584 (retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

PatientID: 4 (Proband)

KindredID: 18

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (38 and 43Y) and pheochromocytoma (20 and 43Y).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: Supplementary Table 1.

Variant: 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: 2

KindredID: 1

Case: F, 38Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 3 other family members were included in this study and all had the same VHL variant. Patient 3 (Gen 2) presented with bilateral pheochromocytoma and died due to a ruptured aortic aneurysm of Takayasu arteritis. Patient 4 (Gen 2) presented with bilateral pheochromocytoma. Patient 1 (Gen 2) presented with bilateral pheochromocytoma and sympathetic paraganglioma and PNET.

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

CasePresentingHPOs: HP:0002666; HP:0030405 (Pheochromocytoma, Pancreatic endocrine tumor)

CaseHPOFreeText: Unilateral pheochromocytomaMetastasis found at age 38. Died due to metastatic PNET.

CaseNotHPOs: HP:0005584; HP:0001737; HP:0009711; HP:0010797; HP:0002668 (Renal cell carcinoma, Pancreatic cysts, Retinal capillary hemangioma, Hemangioblastoma, Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: II-4

KindredID: 3

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's mother (I-2) died as a result of pancreatic cancer. The eldest sister of the patient (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another sister (II-2) underwent surgery for breast cancer. The patient's two sons (III-6 and III-7) were found to harbour their father's VHL mutation. See Figure 3 for family pedigree.

CasePresentingHPOs: HP:0006770, HP:0001737, HP:0009713, HP:0000107, HP:0000787 (clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, renal cysts, nephrolithiasis)

CaseHPOFreeText: The patient was treated for kidney stones at age 33. At age 38 he was found to have a mass in the right kidney. Upper abdominal CT revealed the presence of multiple nodules and lumpy low-density areas in the left and right kidneys with uneven density. Multiple round low-density lesions were observed in the left and right kidneys, and in the pancreas. Brain CT revealed no abnormalities, but sphenoiditis was observed on the right side. Thoracic MRI revealed a round-shaped mixed signal (diameter, 12.0 mm) in the sixth thoracic vertebra. Contrast-enhanced scanning revealed minor enhancement, which appeared to indicate the presence of a hemangioma. Postoperative pathological analysis confirmed that the tumor was a clear cell renal cell carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

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: 128

KindredID: 48

Case: M, Age 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband had two family members who passed away before they could be confirmed with the mutation, but presented with VHL disease phenotypes. His father (patient 129) presented with renal cell carcinoma at age 58, and his daughter (patient 130) presented with a CNS hemangioblastoma at 13.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 32, renal cell carcinoma and multiple pancreatic cysts/tumors at 38, and pheochromocytoma at 40.

CaseNotHPOs: HP:0009711 (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: p.L135* (c.404T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754021; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L135* (c.404T>A)

MultipleGeneVariants: N/A

PatientID: None (proband 11)

KindredID: 11

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s mother (last known age 36Y) had a CNS hemangioblastoma diagnosed at 36Y.

CasePresentingHPOs: HP:0005584; HP:0001737 (renal cell carcinoma, pancreatic cysts)

CaseHPOFreeText: RCC and multiple pancreatic cysts or tumors diagnosed at age 34 and 38Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 22357542

SupplementalData: N/A

Variant: p.W88* (c.263G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, 38Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 1, patients 2 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

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

CaseHPOFreeText: The patient developed PPGL at 38Y of age, and a PNET at 38Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114S (c.340G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G114S (c.340G>A)

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: 192

KindredID: 73

Case: F, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 191, has a mother who was also found to have the same germline mutation. The proband's mother (patient 192) had a retinal angioma at 25, a CNS hemangioblastoma at 38, and multiple pancreatic cysts/tumors at 52.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 38, retinal angioma at 25, and multiple pancreatic cysts/tumors at 52.

CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as 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.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: 290

KindredID: 114

Case: M, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0009711 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Retinal capillary hemangioma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 38, and at age 41 presented with a retinal angioma, renal cell carcinoma, and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666 (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: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 81

KindredID: 27

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 81) had 3 family members confirmed with the mutation: his aunt 2 (patient 85) had pancreatic cysts and/or tumors at age 50, his cousin/ the son of Aunt 2 was asymptomatic at the time of assessment, and the granddaughter of aunt 2 was also asymptomatic at the time of assessment. The proband also had 3 family members who passed away before diagnosis/ before confirming the mutation: his mother (patient 82) had a CNS hemangioblastoma at 33, his Aunt 1 (patient 83) had a CNS hemangioblastoma at 32, and his cousin/ the son of Aunt 1 (patient 84) had a CNS hemangioblastoma at 30.

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

CaseHPOFreeText: The proband presented with CNS hemangioblastoma at age 28, and renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 38.

CaseNotHPOs: HP:0009711(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: p.N90I (c.269A>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: 5

KindredID: 3 (C)

Case: F, 38Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Family C consists of two parents and their two daughters. Patient's 14 year old daughter (see patient 4) shares the same mutation as him. She developed a retinal angioma at 12 years of age and a spinal cord hemangioma was detected at 14 years. The mother and the other daughter were free from any manifestations of the disease and showed no mutations in the VHL gene.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0006770 (spinal hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, clear cell renal cell carcinoma)

CaseHPOFreeText: Radiological investigations detected bilateral kidney tumors, a cerebellar and a spinal cord hemangioma at 34 years of age. Histological analysis of the kidney verified RCC. Four years later (38 years of age), retinal angioma developed in both of his eyes.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA357042 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B1G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.340+1G>A

MultipleGeneVariants: N/A

PatientID: III:4

KindredID: 1

Case: M, 56Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

CasePresentingHPOs: HP:0006880; HP:0002666 (cerebellar hemangioblastoma; pheochromocytoma)

CaseHPOFreeText: patent had a combination of cerebellar HB and bilateral pheo, age of onset at 38Y, and operated on the same year

CaseNotHPOs: HP:0006880; HP:0002666; HP:0030405; HP:0001737; HP:0000107; HP:0002668 (pancreatic endocrine tumor, pancreatic cysts, renal cysts, paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: Sex Unknown, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had family history of VHL disease. The patient’s aunt and her son had the same mutation, but no clinical manifestations. The patient’s mother, another aunt and her son had hemangioblastomas at age 30, 33, and 32, respectively, but died prior to genetic testing could be performed.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

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

CaseHPOFreeText: The patient presented with a hemangioblastoma at age 28, as well as renal cell carcinoma at age and abnormality of the pancreas at age 38.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: 9

KindredID: 9

Case: Sex Unknown, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive family history. The patient's mother had the same VHL mutation and presented with CNS hemangioblastoma.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

CasePresentingHPOs: HP:0006770, HP:0001732 (clear cell renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText: The patient presented with clear cell renal cell carcinoma at age 34 and multiple pancreatic cysts or tumours at age 38.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0010797 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24986515

SupplementalData: N/A

Variant: p.W88* (c.263G>A)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName:W88*(c.263G>A)

MultipleGeneVariants: N/A

PatientID: None (sister)

KindredID: 10

Case: F, 38Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Patient had a positive family history: Her father was died of RCC (no mutation availible), and her older sister who presented with spinal HB and multiple cysts in pancreas and both kidneys, harbored the same exon deletion

CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseHPOFreeText: presented with medullary HB at the age of 37 and multiple RCC in both kidneys at the age of 38

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1-3 deletion (c.1-?_642+?del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 44Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient has a notable family history. Her eldest brother had multiple RCCs in both kidneys, bilateral cerebellar hemangioblastomas, and pheochromocytoma in his left adrenal gland (see Patient 2). Her daughter also underwent cortex-sparing adrenalectomies for bilateral pheochromocytomas as well as hemangioblastoma resection in her left cerebellum at age of 19 years, although no testing for VHL was stated.

CasePresentingHPOs: HP:0006748, HP:0030405, HP:0006880, HP:0000107, HP:0005584 (adrenal pheochromocytomas, pancreatic endocrine tumour, cerebellar hemangioblastoma, renal cyst, renal cell carcinoma)

CaseHPOFreeText: Patient diagnosed at age 29 with bilateral pheochromocytomas when she presented with severe hypertension and two large masses (greater than 6 cm) in her bilateral adrenal glands. At 38 years old, she underwent a resection for a mass found on her pancreas, with pathological analysis of the mass revealing a pancreatic neuroendocrine tumor. At 42 years old, a follow-up CT scan revealed two heterogeneous contrast-enhanced masses, one on the right kidney and one on the left adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

ClinVar: 625229 https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAiD: CA16621914 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 38Y0M, German

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo:All patients from the German registry for VHL with PNETs >3 cm diameter with tumours located in the pancreatic body or tail region.

CasePresentingHPOs: HP:0009711, HP:0009713, HP:0006880, HP:0009726, HP:0030405, HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm, pancreatic endocrine tumour, pancreatic cysts)

CaseHPOFreeText: Retinal angiomatosis at age 17, hemangioblastoma of the cervical spinal cord at age 24, cerebellar hemangioblastoma at age 27, left renal tumor at age 36. Pancreatic endocrine tumour and pancreatic cysts at age 38. She had a laparoscopy which found an 8-cm retrogastric cyst, 3.2-cm benign PNET, and a serous cystadenoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q132* (c.394C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q132* (c.394C>T)

MultipleGeneVariants: N/A

GroupID: 51

Case: 38Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.193T>C) was found in 1 VHL family with a single patient.

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

CaseHPOFreeText: patient had retinal hemangioblastoma at age 38, and cerebellar hemangioblastoma at age 38.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65P (c.193T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 547829 https://www.ncbi.nlm.nih.gov/clinvar/variation/547829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 147

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 147

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121Mfs*38 (c.361delG)

CaseProblemVariantFreeText: N/A

LegacyVariant: FS (c.574delG)

ClinVarID: N/A

CAID: CA432421803 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: D121Mfs*38 (c.361delG)

MultipleGeneVariants: N/A

PatientID: IV-6

KindredID: 1

Case: F, 38Y0M, Chinese

DiseaseAssertion: Glioblastoma

FamilyInfo: Eight affected individuals in the patient’s family were retrospectively identified by reviewing medical records and from the recall of relatives. Three had passed away before 40 years of age because of central nervous system hemangioblastoma. Among the 10 living family members that carried the same NM_000551.3:c.326_339dupTCCACAGCTACCGA the patient carried, 3 had renal cysts and 1 had developed renal cell carcinoma, 2 had central nervous system hemangioblastoma, 1 had retinal hemangioblastomas, 1 was diagnosed with glioblastoma, and 5 were asymptomatic.

CasePresentingHPOs: ORPHA:360 (Glioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584 (Retinal hemangioblastoma, hemangioblastoma, renal cyst, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Gly114Serfs*50(c.326_339dupTCCACAGCTACCGA)

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2573051018 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051018

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: G114fs (c.326_339dupTCCACAGCTACCGA)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: B

Case: Sex Unknown, 42Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

CasePresentingHPOs: HP:0010797, HP:0005584 (hemangioblastoma, renal cell carcinoma

CaseHPOFreeText: The patient had a hemangioblastoma diagnosed at age 30. The patient was diagnosed with renal cell carcinoma at age 38. A nephron-sparing surgery was performed on the left side. He was found to have one lesion with a diameter of 5.5 cm. The tumour had invaded and broken through the pseudocapasule. The patient was found to have a cyst on the right nephron.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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: None (Cousin 2)

KindredID: G

Case: Sex Unknown, 38Y0M, Hungarian

DiseaseAssertion: Assumed VHL

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

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

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 38, pheochromocytoma at age 39 and retinal hemangioblastoma at age 29. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 6

Case: F, 38Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with a juxtapapillary tumor in her left eye at the age of 38.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Information obtained from Table 2.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 24

KindredID: 3775

Case: F, 39Y3M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with 1 radiographic pancreatic neuroendocrine tumor diagnosed at age 38Y. Follow up 15M after EN surgery, currently no evidence of disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128F (c.381_382delinsTT)

LegacyVariant: p.L>F (c.594_595GC>TT)

CaseProblemVariantFreeText: N/A

ClinVarID: 223203 https://www.ncbi.nlm.nih.gov/clinvar/variation/223203

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName: L128F (c.381_382delinsTT)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: assumed VHL

GroupSize: 15

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 36.9Y +/- 15.6Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 3 families with 15 members total were described, and phenotypic information was given for this group.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, pheochromocytoma)

GroupHPOFreeText: 10 of the 15 members presented with CNS hemangioblastoma (mean age of 29.9Y), 2/15 had retinal capillary hemangiomas at 23Y and 30Y, renal cell carcinoma in 4 members (at a mean age of 41.5Y), pancreatic cysts in 5 members (with a mean age of onset of 41.4Y), and 1 member with pheochromocytoma at 38Y

GroupNotHPOs: HP:0009715 (papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No patients were given with papillary cystadenoma of the epididymis

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336; 28388566

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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;transition

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

GroupID: 22

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family. 

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

GroupHPOFreeText: 1 patient had retinal angiomas diagnosed at the age of 15Y, 1 had cerebellar hemangioblastomas diagnosed at 20Y, and 1 member had RCC diagnosed at 38Y.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.H125Qfs*7 (c.374dupA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2499307153 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307153

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: H125fs (c.374insA) 

MultipleGeneVariants: N/A

GroupID/ KindredID: 1

Case: Age, Sex, Swedish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584; HP:0002666 (renal cell carcinoma; pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S38P (c.112T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351747824 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.112T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S38P (c.112T>C)

MultipleGeneVariants: N/A

PatientID: 2 (II:2)

KindredID: 1

Case: F, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: large family history of VHL was tested - 3 members found. The patient's brother and her daughter had the same mutation - Her brother (patient 1) was diagnosed with spinal hemangioblastoma, and at 43Y he was diagnosed with ccRCC in his right kidney

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0000107; HP:0001737 (hemangioblastoma, clear cell renal cell carcinoma; renal cysts; pancreatic cysts)

CaseHPOFreeText: had cerebellum hemangioblastoma at 38Y and a neoplasm of both kidneys at 40Y, as well as ccRCC, renal and pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 22398592

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: L101R (c.515T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 8

Case: M, 38Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0000107; HP:0002172; HP:0001288 (Cerebellar hemangioblastoma, Pancreatic cysts, Renal cyst, Postural instability, Gait disturbance)

CaseHPOFreeText: At 38Y, this patient showed mild imbalance with gait difficulty. MRI of the brain revealed a cystic mass in the cerebellum, which was pathologically found to be hemangioblastoma. When this patient underwent CT, which included the pancreas and kidney, multiple pancreatic cysts and renal cysts were found. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223221, https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transversion

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

MultipleGeneVariants: N/A

Reply to Orga A 38 1908 r!!<br /> by Neat_Substance_2084 at https://old.reddit.com/r/typewriters/comments/1wsmhar/orga_a_38_1908_r/

From what I've seen, your only evidence of your claim are a poorly hand scratched marking and some metallurgic tests.

You need a lot more evidence than what you're presenting to prove your claim, particularly given the decade and change of the passing of time.

I can scratch a 1940 date onto my Olympia SM3, but it doesn't mean that it's a prototype from 13 years earlier. Your presumed date is also of the form of an accounting ledger and not one that a mechanic would have scratched in.

Do you have any provenance on your machine? (Who owned it and when?)

Do you have any paperwork from the designers? Patents?

The material tests only show a difference in the metal content, they don't indicate a date of any sort. If they could, you'd need a lot more material research on manufacturing methods and timelines from the historical record to back it up. Typewriter manufacturers were constantly changing their manufacturing lines and designs to make them more efficient and less expensive to improve their bottom lines, so your material science differences would seem par for the course. Can you show similar changes in materials from the companies toy lines over the same period?

You seem to be only sharing blurry photos of screens rather than direct documentation of your material difference claims. Where are the direct documents and which company did the testing?

Given the tremendous amount of focus on design changes and patents in early typewriter manufacturing and sales, how does the design of your machine fit into the early aughts from 1900-1910 versus 1920 and on? Typewriter designs had settled down significantly by the early 1920s, so there should be some reasonably significant design differences between a 1908 machine and one from 1923. Where have you documented those?

What company history physically exists? When did they begin design? When were they producing prototypes in general? 13 years of R&D is a tremendous amount of time to pass in typewriter design in the early 1900s before manufacturing of any sort, even if you discount stoppages for World War I. Are there extant notebooks or corporate papers from the time period you're claiming? They were manufacturing toys for decades prior, so surely they've got some reasonable corporate documentation and correspondence somewhere. Do any of the descendants have papers, receipts, or diaries that could be consulted? What were the market conditions that suggested to them that a move from toys to typewriters was a brilliant idea? Often in a prototype situation, a factor may not have all the manufacturing capabilities in-house or they'd need to make changes to equipment to make a new line. Are there pieces of your typewriter that were outsourced from other factories? Is there evidence that all the parts of the later machines were made in-house?

Think like an archaeologist. Think like a historian. Bring some more research to bear if you want to convince anyone (experts or otherwise) of your claims. It should seem painfully obvious to you by now that what you're presenting is not nearly enough. No one is attacking you. We're just asking for more if we're going to be convinced.

Todd Blanche hit with state bar complaint backed by 101 former judges<br /> by [[Steve Benen]]<br /> accessed on 2026-06-24T00:19:53

Who was Shevchenko? What did he write?

1:33:38 When there is new EVIDENCE, we CHANGE OUR MIND

1:22:36 Could A community Association get a Community Banking Licence? 1:22:38 Could a local Credit Union be a consortium partner and issue more money into the system to develop the entire wealth of the Neighbourhood

for stats - digital stats - 38% of webpages in 2013 no longer exist May 2024

AssayResult: 3.8

AssayResultAssertion: Indeterminate

StandardErrorMean: 0.18

HGVS: NM_024675.3:c.2798G>A p.(Cys933Tyr)

AssayResult: 85

AssayResultAssertion: Not reported

PValue: Not reported

Approximation: Exact assay result value not reported; value estimated from Figure 6C.

AssayResult: 3

AssayResultAssertion: Indeterminate

PValue: Not reported

AssayResult: 82.06

AssayResultAssertion: Indeterminate

PValue: 0.0058

Comment: Exact values reported in Table S3.

HGVS: NM_024675.3:c.53A>G p.(Lys18Arg)

AssayResult: 80.44

AssayResultAssertion: Not reported

ReplicateCount: 2

StandardErrorMean: 9.06

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

AssayResult: 97.37

AssayResultAssertion: Not reported

ReplicateCount: 2

StandardErrorMean: 5.14

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

AssayResult: 95.16

AssayResultAssertion: Not reported

ReplicateCount: 3

StandardDeviation: 16.94

StandardErrorMean: 9.78

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

HGVS: NM_024675.3:c.2993G>A p.(G998E)

AssayResult: 36

AssayResultAssertion: Abnormal

ReplicateCount: 19

StandardErrorMean: 5.9

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.3673G>A p.(Glu1225Lys)

AssayResult: 94

AssayResultAssertion: Normal

Comment: See Table S2 for details

AssayResult: 2.8

AssayResultAssertion: Abnormal

Comment: See Table S2 for details

HGVS: NM_000546.5:c.742C>T p.(Arg248Trp)