21 Matching Annotations
  1. Last 7 days
  2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Germ‐line Mutation Analysis in Patients with von Hippel‐Lindau Disease in Japan: An Extended Study of 77 Families
    1
    1. ClingenBaseline 13 Nov 2026

      PatientID: None

      KindredID: 67

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L198Gfs*57 (c.592_593del)

      LegacyVariant: c.805_806del

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658795185, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.592_593del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion; minus_2_framshift_variant

      CivicName: L198Gfs*57 (c.592_593del)

      MultipleGeneVariants: N/A

      InheritancePattern:AutosomalDominant Ethnicity:Japanese DiseaseEntity:VHL DiseaseEntity:hemangioblastoma DiseaseEntity:renalcellcarcinoma DiseaseEntity:retinalcapillaryhemangioma DiseaseEntity:abnormalityofthepancreas Mutation:Germline RefSeq:AF010238.1 cDNAposition:592 ProteinPosition:198 AminoAcidChange:LEUtoGLY ClinVarID:N/A CAID:CA658795185 MutationType:deletion MutationType:minus_2_frameshift_variant CivicName:L198Gfs*57(c.592_593del) NoFamilyInfo inferred_gene_hgnc:12687 inferred_gene_source:CAID VHL Hypothesis Annotation
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    pubmed.ncbi.nlm.nih.gov/10761708/
  3. Nov 2026
  4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan
    1
    1. ClingenBaseline 03 Nov 2026
      Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 110CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 110CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, ithout phechromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL familywith RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G57Rfs*75 (c.167_168insA)

      LegacyVariant: (c.380insA)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA916084344 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.167_168insA

      gnomAD: N/A

      VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

      MutationType: plus_1_frameshift_variant

      CivicName: G57fs (c.167_168insA)

      MultipleGeneVariants: N/A

      InheritancePattern:AutosomalDominant Mutation:Germline RefSeq:AF010238.1 DiseaseEntity:renalcellcarcinoma cDNAposition:167 ProteinPosition:57 MutationType:plus_1_frameshift_variant AminoAcidChange:GLYtoARG CAID:CA916084344 ClinVarID:N/A Familial CivicName:G57fs(c.167_168insA) FamilyCohort inferred_gene_hgnc:12687 inferred_gene_source:CAID VHL Hypothesis Annotation
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    pubmed.ncbi.nlm.nih.gov/8956040/
  5. cancerres.aacrjournals.org cancerres.aacrjournals.org
    Telomere Shortening Is Associated with Genetic Anticipation in Chinese Von Hippel–Lindau Disease Families
    1
    1. ClingenBaseline 03 Nov 2026
      c.533T>G p.Leu178Arg

      PatientID: None (proband 10)

      KindredID: 10

      Case: M, 57Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Patient’s son was found with the same mutation, as well as RCC diagnosed at 30Y

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

      CaseHPOFreeText: patient had hemangioblastoma diagnosed at 39Y, as well as retinal capillary hemangioma, renal cell carcinoma and pancreatic cysts diagnose at 57Y

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L178R (c.533T>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 625261 https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: L178R (c.533T>G)

      MultipleGeneVariants: N/A

      InheritancePattern:AutosomalDominant Familial Ethnicity:Chinese DiseaseEntity:VHL DiseaseEntity:hemangioblastoma DiseaseEntity:retinalcapillaryhemangioma DiseaseEntity:renalcellcarcinoma DiseaseEntity:pancreaticcysts AgeOfPresentation:hemangioblastoma:39 AgeOfPresentation:retinalcapillaryhemangioma:57 AgeOfPresentation:renalcellcarcinoma:57 AgeOfPresentation:pancreaticcysts:57 ClinVarID:625261 ClinVarID:Yes Mutation:Germline AssumedRefSeq:NM_000551.3 ExperimentalAssay CivicName:L178R(c.533T>G) cDNAposition:533 ProteinPosition:178 AminoAcidChange:LEUtoARG MutationType:missense_variant;transversion inferred_gene_hgnc:12687 inferred_gene_source:ClinVar VHL Hypothesis Annotation
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    cancerres.aacrjournals.org/content/74/14/3802
  6. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL) syndrome type 2C
    1
    1. ClingenBaseline 01 Nov 2026
      History showed that the patient's father had undergone a resection of the right adrenal gland at the age of 48 because of a pheochromocytoma.

      PatientID: None

      KindredID: 1

      Case: M, 48Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: The patient’s daughter had bilateral adrenal pheochromocytoma at 27Y, and was found to have bilateral small lesions suspicious for inactive retinal angiomas upon further investigation. Genetic testing found that the patient’s daughter carried the same NM_000551.3:c.277G>A mutation that the patient was found to carry. The patient’s granddaughter was also found to carry the mutation. The patient's mother had also died at 42Y as a result of a stroke, and the patient’s uncle had died at 57Y as a result of a stroke. There is no genetic information available about them. The other daughter of the patient did not carry the mutation.

      CasePresentingHPOs: HP:0006748; HP:0030424; HP:0000107 (Adrenal pheochromocytoma, epididymal cyst, renal cyst)

      CaseHPOFreeText: The 48Y male patient presented with a right adrenal pheochromocytoma at 48Y. Further investigation revealed left epididymal cysts and bilateral renal cysts.

      CaseNotHPOs: HP:0009713; HP:0009711 (Spinal hemangioblastoma, retinal hemangioblastoma)

      CaseNotHPOFreeText: An MRI of the brain and spinal cord showed no signs of hemangioblastomas and examination of the eyes showed no retinal hemangioblastomas.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G93S (c.277G>A)

      LegacyVariant: N/A

      ClinVarID: 2237, https://www.ncbi.nlm.nih.gov/clinvar/variation/2237/

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G93S(c.277G>A)

      MultipleGeneVariants: N/A

      InheritancePattern:AutosomalDominant DiseaseEntity:VHL DiseaseEntity:adrenalpheochromocytoma DiseaseEntity:renalcyst DiseaseEntity:epididymalcyst AgeOfPresentation:adrenalpheochromocytoma:57 AgeOfPresentation:renalcyst:57 AgeOfPresentation:epididymalcyst:57 Mutation:Germline RefSeq:N/A cDNAposition:277 ProteinPosition:93 AminoAcidChange:GLYtoSER ClinVarID:2237 ClinVarID:Yes MutationType:missense_variant;transition CivicName:G93S(c.277G>A) FamilyPedigree Familial inferred_gene_hgnc:12687 inferred_gene_source:ClinVar VHL Hypothesis Annotation
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    ncbi.nlm.nih.gov/pmc/articles/PMC2169240/
  7. Oct 2026
  8. jmg-bmj-com.uhn.idm.oclc.org jmg-bmj-com.uhn.idm.oclc.org
    Evidence for genetic anticipation in vonHippel-Lindau syndrome
    1
    1. ClingenBaseline 31 Oct 2026

      PatientID: 9 (Grandmother)

      KindredID: 13

      Case: F, 67Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 5 members of this family were found to harbour the deletion of one VHL allele. The proband (ID 1), sister (ID 2) and uncle (ID 5) were all asymptomatic. The father (ID 3) presented with CNS hemangioblastoma (34Y).

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: This patient presented with CNS hemangioblastoma (57Y).

      CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0000077; HP:0001732 (Pheochromocytoma, Renal cell carcinoma, Retinal capillary hemangioma, Abnormality of the kidney, Abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table 1.

      Variant: Complete Deletion

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Reported as “del one vHL allele”.

      MutationType: deletion

      CivicName: Null (del one VHL allele)

      MultipleGeneVariants: N/A

      InheritancePattern:AutosomalDominant DiseaseEntity:VHL DiseaseEntity:hemangioblastoma AgeOfPresentation:hemangioblastoma:57 Mutation:Germline AssumedRefSeq:NM_000551.3 cDNAposition:N/A ProteinPosition:N/A AminoAcidChange:N/A ClinVarID:N/A MutationType:deletion Familial UnregisteredVariant CivicName:Null(deloneVHLallele) inferred_gene_hgnc:12687 inferred_gene_source:RefSeq VHL Hypothesis Annotation
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    jmg-bmj-com.uhn.idm.oclc.org/content/55/6/395
  9. jnccn.org jnccn.org
    Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation
    1
    1. ClingenBaseline 30 Oct 2026
      Case ReportA 57-year-old Caucasian woman with an unremarkable past medical history presented with lumbar pain. Physical examination revealed a mass on the right flank. An FDG-PET scan revealed a renal mass highly suggestive of malignancy, signs of liver spread, and pelvic and lumbar spinal cord bone metastases (Figure 1A). Tumor staging at initial diagnosis was pT1bN0M1 (stage IV). In April 2007, an open right radical nephrectomy was performed. The histopathologic report revealed Fuhrman grade 4 advanced ccRCC. According to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic model,14 the patient was classified as being in the intermediate-risk group based on 2 risk factors for the prognostic score: Karnofsky performance status of 70% and a serum lactic dehydrogenase level >1.5 times the upper limit of normal. She received palliative radiotherapy View Full Size Figure 1.(A) Initial tumor dissemination detected by PET/CT (arrows). (B) MRI showing skull metastasis (arrow), which was surgically removed in 2015.Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 11; 10.6004/jnccn.2017.7018Download FigureDownload figure as PowerPoint slideFigure 1.(A) Initial tumor dissemination detected by PET/CT (arrows). (B) MRI showing skull metastasis (arrow), which was surgically removed in 2015.Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 11; 10.6004/jnccn.2017.7018Download FigureDownload figure as PowerPoint slide for a painful right iliac metastasis and started sunitinib treatment at 50 mg/d on a 4 weeks on, 2 weeks off schedule (4/2). After 2 cycles, all tumoral lesions had progressed and treatment was switched to sorafenib, 400 mg twice daily. New response assessment after 2 cycles revealed disease progression with new liver and bone lesions and clinical deterioration. In March 2008, the patient started temsirolimus at 25 mg weekly and experienced a remarkable clinical benefit. She had a partial response according to RECIST criteria, with a time to best response after starting temsirolimus of 6 weeks (temsirolimus start: March 3, 2008; response at first reevaluation: April 16, 2008), and experienced overall good tolerance; she continued temsirolimus for >7 years. Main toxicity consisted of 3 different pneumonitis episodes (grade 1–3) that required dose interruptions or reductions. In August 2015, a new solitary bone metastasis arose in the skull, whereas others remained with no change (Figure 1B). A complete resection of the lesion was performed followed by local radiotherapy. At 21 months after the metastasectomy, the patient continues on treatment with biweekly temsirolimus in combination with denosumab, with no tumor progression.We performed WES in 3 different regions of the primary tumor obtained before treatment, in the skull metastasis resected 7 years after temsirolimus treatment initiation, and in the germline DNA obtained from the patient's blood. The mean depth of coverage was >80x for the 3 regions of the primary tumors, 136x for the metastasis, and 94x for the blood (see supplemental eAppendix 1 for details regarding methodology, available online with this article at JNCCN.org). The number of tumor mutations (single nucleotide variants and indels) leading to nonsynonymous coding or loss-of-function (LOF) variants in the primary tumor was 160. Tumor mutations refer to those detected in the tumor but absent in the blood. In total, 116, 76, and 65 mutations were detected in each of the 3 tumor regions and from these, 41 were shared (Figure 2; supplemental eTable 1). Among the shared tumor mutations, 39 were missense variants and 2 were LOF variants caused by frameshifts. The variants affecting genes frequently mutated in ccRCC were detected in all tumor samples analyzed: VHL (c.263G>T; p.W88L), BAP1 (c.1359dup; p.E454Rfs*15), and MTOR (c.5920T>C; p.Y1974H), and were validated by Sanger sequencing. In ccRCC the primary driver event is VHL inactivation, and thus VHL mutations are early alterations present in all tumor cells.15 The MTOR mutation frequencies detected in the different tumor samples sequenced were similar to those found for VHL, indicating that the MTOR mutation was also a truncal event in this patient (average ratio of 1.1; supplemental eTable 1). View Full Size Figure 2.Mutations revealed by whole-exome sequencing (WES). (A) Venn diagram indicating the number of tumor (absent in blood) loss-of-function and nonsynonymous coding variants identified through WES in 3 regions (R1–R3) of the primary tumor. Shared variants affecting relevant clear cell renal cell carcinoma genes are indicated below the arrow. (B) Representative genome images from the Integrative Genomics Viewer (Broad Institute), along with the number of reads for the reference (ref) and variant allele of the MTOR Y1974H mutation, and Sanger sequencing chromatogram.Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 11; 10.6004/jnccn.2017.7018Download FigureDownload figure as PowerPoint slideFigure 2.Mutations revealed by whole-exome sequencing (WES). (A) Venn diagram indicating the number of tumor (absent in blood) loss-of-function and nonsynonymous coding variants identified through WES in 3 regions (R1–R3) of the primary tumor. Shared variants affecting relevant clear cell renal cell carcinoma genes are indicated below the arrow. (B) Representative genome images from the Integrative Genomics Viewer (Broad Institute), along with the number of reads for the reference (ref) and variant allele of the MTOR Y1974H mutation, and Sanger sequencing chromatogram.Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 11; 10.6004/jnccn.2017.7018Download FigureDownload figure as PowerPoint slide View Full Size Figure 3.Functional assessment of MTOR p.Y1974H variant. Constructs expressing wild-type (WT) mTOR, mTOR Y1974H, and mTOR S2215Y (a positive control for mTOR activation) were transfected in HEK293 cells and the effect of phosphorylation of the downstream target S6K1 (pS6K1) was tested with Western blot. (A) Western blot analysis 24 hours after transfection cells were serum-starved for 24 hours (Starving) and then stimulated with 1% or 10% fetal bovine serum for 2 hours (Stimulation). In the Starving assay, lanes 1–2, 3–4, and 5–6 are duplicates from different experiments. (B) Cells transfected with mTOR constructs were treated with 2.5, 12.5, and 100 nM of rapamycin (rap) for 6 hours.Abbreviation: GAPDH, glyceraldehyde 3-phosphate dehydrogenase.Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 11; 10.6004/jnccn.2017.7018Download FigureDownload figure as PowerPoint slideFigure 3.Functional assessment of MTOR p.Y1974H variant. Constructs expressing wild-type (WT) mTOR, mTOR Y1974H, and mTOR S2215Y (a positive control for mTOR activation) were transfected in HEK293 cells and the effect of phosphorylation of the downstream target S6K1 (pS6K1) was tested with Western blot. (A) Western blot analysis 24 hours after transfection cells were serum-starved for 24 hours (Starving) and then stimulated with 1% or 10% fetal bovine serum for 2 hours (Stimulation). In the Starving assay, lanes 1–2, 3–4, and 5–6 are duplicates from different experiments. (B) Cells transfected with mTOR constructs were treated with 2.5, 12.5, and 100 nM of rapamycin (rap) for 6 hours.Abbreviation: GAPDH, glyceraldehyde 3-phosphate dehydrogenase.Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 11; 10.6004/jnccn.2017.7018Download FigureDownload figure as PowerPoint slide For BAP1 mutation, the average ratio was 0.66. Other genes implicated in cancer with mutations included BCL11B, CIC, EML4, KMT2C, NOTCH1, and RANBP2 (see supplemental eTable 1).To assess the effect of the MTOR novel variant p.Y1974H, HEK293 cells were transfected with constructs expressing the wild-type mTOR protein or the Y1974H variant protein. The mTOR-activating mutation S2215Y was used as control for the experiments. The Thr389 phospho-S6K1 (pS6K1) levels, which represent TORC1 activity, were augmented for the Y1974H variant compared with mTOR wild-type, and similar to those obtained for S2215Y (Figure 3A), indicating that mTOR Y1974H activates mTORC1. In addition, we observed that mTOR Y1974H was sensitive to rapamycin (Figure 3B). mTOR Y1974H also led to an increased number of cells in S phase with a concomitant decrease in G0/G1, and an alteration in forward scatter (data related to an alteration in cell size) compared with mTOR wild-type and similar to mTOR S2215Y (supplemental eFigure 1).16 Immunohistologic analysis of the tumor samples revealed activation of the mTOR pathway through a positive immunostaining of phospho-S6, a downstream target of mTOR (Figure 4A–C), with the metastasis staining being more intense than that in the primary tumor. The staining of p-ERK (Figure4 D–F) was weak in the primary tumor, whereas the metastasis exhibited a nuclear and cytoplasmatic intense and extensive staining.WES of the metastasis that arose 7 years after starting temsirolimus treatment revealed 80 tumor nonsynonymous coding or LOF variants (71 missense, 2 in-frame deletions, and 7 LOF) present in the tumor and absent in the blood. Of these, 51 were shared with the primary tumor and 29 were exclusively present in the metastasis (supplemental eTable 1). Among the genes exclusively mutated in the metastasis, only 3 (CRTC3, KAT6B, PBRM1) were in the Cancer Gene Census (CGC) but none were directly related to the MTOR pathway, and the variants have not been previously described in tumors, according to the COSMIC database.The full region of the MTOR FKBP-rapamycin binding domain (FRB), including intronic regions, was sequenced by Sanger. However, no metastasis-specific variants were detected.

      PatientID: None

      KindredID: 1

      Case: F, 39Y0M, Ethnicity Unknown

      DiseaseAssertion: Clear cell renal cell carcinoma

      FamilyInfo: N/A

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

      CaseHPOFreeText: A 57-year-old Caucasian woman with an unremarkable past medical history presented with lumbar pain. Physical examination revealed a mass on the right flank. An FDG-PET scan revealed a renal mass highly suggestive of malignancy, signs of liver spread, and pelvic and lumbar spinal cord bone metastases. Open right radical nephrectomy was performed. The histopathologic report revealed Fuhrman grade 4 advanced ccRCC. New response assessment after 2 cycles of treatment revealed disease progression with new liver and bone lesions and clinical deterioration. In August 2015, a new solitary bone metastasis arose in the skull, whereas others remained with no change.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary eTable1

      Variant: p.W88L (c.263G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351750675, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351750675

      gnomAD: N/A

      VariantEvidence: VHL and MTOR variants were not explicitly stated to be germline in the text but were not present in Supplementary eTable 1 where variants present in tumor/metastasis and absent in blood are listed. The number of tumor mutations (single nucleotide variants and indels) leading to nonsynonymous coding or loss-of-function (LOF) variants in the primary tumor was 160. Tumor mutations refer to those detected in the tumor but absent in the blood. In total, 116, 76, and 65 mutations were detected in each of the 3 tumor regions and from these, 41 were shared. Among the shared tumor mutations, 39 were missense variants and 2 were LOF variants caused by frameshifts. The variants affecting genes frequently mutated in ccRCC were detected in all tumor samples analyzed: VHL (c.263G>T; p.W88L), BAP1 (c.1359dup; p.E454Rfs*15), and MTOR (c.5920T>C; p.Y1974H). For a comprehensive list of somatic variants see Supplementary eTable1.

      MutationType: missense_variant;transversion

      CivicName: W88L (c.263G>T)

      MultipleGeneVariants: Germline, MTOR, c.5920T>C (p.Tyr1974His) MultipleGeneVariants: Somatic, BAP1, c.1359dup (p.Glu454Argfs*15)

      InheritancePattern:AutosomalDominant DiseaseEntity:clearcellrenalcellcarcinoma AgeOfPresentation:clearcellrenalcellcarcinoma:57 Mutation:Germline AssumedRefSeq:NM_000551.3 cDNAposition:263 ProteinPosition:88 AminoAcidChange:TRPtoLEU ClinVarID:N/A CAID:CA351750675 MultipleGeneVariants MutationType:missense_variant;transversion CivicName:W88L(c.263G>T) PreviousTesting:SupplementaleTable1 NoFamilyInfo SupplementalData inferred_gene_hgnc:12687 inferred_gene_source:CAID VHL Hypothesis Annotation
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    jnccn.org/view/journals/jnccn/15/11/article-p1310.xml
  10. onlinelibrary-wiley-com.uhn.idm.oclc.org onlinelibrary-wiley-com.uhn.idm.oclc.org
    Somatic mutations in VHL germline deletion kindred correlate with mild phenotype
    1
    1. ClingenBaseline 28 Oct 2026
      A→G @ 8678 K→E @159

      PatientID: A (Tumor 2)

      KindredID: 1

      Case: F, 57Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: This kindred with a VHL germline deletion was studied. Apparently inherited from her father and paternal grandmother as they were affected, and passed to daughter but no phenotypic data was provided for these familials. Her sister and nephew also presented with hemangioblastomas and this germline deletion, and further somatic details were studied.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: 2 cerebellar HB surgically resected at 57Y and found with somatic mutations in both tumors

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: no VHL-associated visceral malignancies in the patient

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.K159E (c.475A>G)

      LegacyVariant: c.8678 (p.Lys159Glu)

      CaseProblemVariantFreeText: A somatic mutation in exon 3 (nt: c.8678 (p.Lys159Glu)) via Latif et al.’s (1993) old transcript) was used.

      ClinVarID: 825149 https://www.ncbi.nlm.nih.gov/clinvar/variation/825149/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: unspecified germline deletion as demonstrated by FISH analysis. “Second-hit” tumorigenesis displayed due to somatic mutation found, which was not predicted by the specific germline deletion nor by the overall genetic composition of the patient. Both of this patient’s cerebellar tumors had somatic mutations.

      MutationType: missense_variant; transition

      CivicName: Deletion

      MultipleGeneVariants: Germline, VHL, deletion; Somatic, VHL, c.903_904insT (p.*151)

      InheritancePattern:AutosomalDominant DiseaseEntity:cerebellarhemangioblastoma AgeOfPresentation:cerebellarhemangioblastoma:57 Mutation:Somatic RefSeq:AF010238.1 CivicName:DELETION ClinVarID:825149 ClinVarID:Yes ProteinPosition:159 cDNAposition:475 AminoAcidChange:LYStoGLU MutationType:missense_variant;transition MultipleVHLVariants Familial FamilyPedigree inferred_gene_hgnc:12687 inferred_gene_source:ClinVar VHL Hypothesis Annotation
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    onlinelibrary-wiley-com.uhn.idm.oclc.org/doi/full/10.1002/ana.10807
  11. Mar 2026
  12. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Progressive mural cell deficiencies across the lifespan in a foxf2 model of cerebral small vessel disease
    1
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    pmc.ncbi.nlm.nih.gov/articles/PMC12965718/
  13. Jan 2025
  14. usrussiarelations.org usrussiarelations.org
    1697: First Contact: The Russian Empire and America, 1698–1917
    1
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    usrussiarelations.org/2/timeline/the-soviet-period/30
  15. Dec 2022
  16. taz.de taz.de
    Deutsche Vorschriften für Windenergie: Energiewende auf Abstand
    1
    1. HeinzWittenbrink 12 Dec 2022

      In Deutschland scheitert der Ausbau der Windkraft nach wie vor an Vorschriften und an mangelndem Engagement von Landes-, aber auch Bundesbehörden. Die taz dokumentiert die aktuelle Lage ausführlich, unter anderem mit einer interaktiven Karte, die zeigt, wo Windkraftanlagen möglich wären. Sie hat dazu Claudia Kemfert und Thorsten Lenk von Agora Energiewende befragt.

      process: energy transition Parameter: Gigawatt time: 2023-2040 Mode: plan datapoints: 57-120
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    taz.de/Deutsche-Vorschriften-fuer-Windenergie/!5901969/
  17. Mar 2021
  18. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Functional characterization of 84 PALB2 variants of uncertain significance
    2
    1. shannon_mcnulty 18 Mar 2021
      Results for individual PALB2 variants were normalized relative to WT-PALB2 and the p.Tyr551ter (p.Y551X) truncating variant on a 1:5 scale with the fold change in GFP-positive cells for WT set at 5.0 and fold change GFP-positive cells for p.Y551X set at 1.0. The p.L24S (c.71T>C), p.L35P (c.104T>C), p.I944N (c.2831T>A), and p.L1070P (c.3209T>C) variants and all protein-truncating frame-shift and deletion variants tested were deficient in HDR activity, with normalized fold change <2.0 (approximately 40% activity) (Fig. 1a).

      AssayResult: 5.1

      AssayResultAssertion: Normal

      StandardErrorMean: 0.56

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:57 CAID:CA288472 ClinVarID:126726
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    ncbi.nlm.nih.gov/pmc/articles/PMC7056643/
  19. www.nature.com www.nature.com
    Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2
    3
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    nature.com/articles/s41467-019-13194-2
  20. www.cell.com www.cell.com
    High-Throughput Reclassification of SCN5A Variants
    2
    1. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.3

      AssayResultAssertion: Abnormal

      ReplicateCount: 24

      StandardErrorMean: 0.3

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

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:57 CAID:CA018079 ClinVarID:67876
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    cell.com/ajhg/fulltext/S0002-9297(20)30162-2
  21. Sep 2020
  22. www.sciencedirect.com www.sciencedirect.com
    BMP Signaling Gradient Scaling in the Zebrafish Pectoral Fin
    2
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    sciencedirect.com/science/article/pii/S2211124720303387
  23. Jul 2017
  24. support.mozilla.org support.mozilla.org
    Firefox add-on technology is modernizing | Firefox Help
    1
    1. Zubaidullo 26 Jul 2017
      Firefox add-on technology is modernizing

      Note: Starting in Firefox 57, which will be released in November 2017, only add-ons built with this new technology will work in Firefox. These are indicated by the “Compatible with Firefox 57+” label on addons.mozilla.org (AMO). Add-ons built with the old technology are labeled “Legacy” on the about:addons tab. If an add-on does not have the "Compatible with 57+" label, or has the "Legacy" label, the developer may be in the process of transitioning to the new technology. You may find developer contact information on the right side of the add-on listing on AMO.

      firefox add-on Firefox 57 release info e2e plugin add-ons browser
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    support.mozilla.org/en-US/kb/firefox-add-technology-modernizing
  25. Oct 2016
  26. vk.com vk.com
    Conversations
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    1. npocmoe.cepoe 13 Oct 2016
      Online

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