This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. This variant is similar to WT1 p.Arg467Pro, which also substitutes a non-polar amino acid for the charged polar Arg and was classified Pathogenic in ClinVar (VCV000003491.3). ClinVar accession VCV000419332.13 classifies WT1 p.Arg467Gln as Likely Pathogenic/Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_024426.6(WT1):c.1400G>T (p.Arg467Leu)
Germline
No data submitted for germline classification
Somatic
Clinical impact
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
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Stars represent the aggregate review status, or the level of review supporting the aggregate somatic clinical impact for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024426.6(WT1):c.1400G>T (p.Arg467Leu)
Variation ID: 3024186 Accession: VCV003024186.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 32392019 (GRCh38) [ NCBI UCSC ] 11: 32413565 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Somatic - Clinical impact Mar 5, 2024 Mar 5, 2024 Jan 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024426.6:c.1400G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077744.4:p.Arg467Leu missense NM_000378.6:c.1349G>T NP_000369.4:p.Arg450Leu missense NM_001198551.2:c.749G>T NP_001185480.1:p.Arg250Leu missense NM_001198552.2:c.698G>T NP_001185481.1:p.Arg233Leu missense NM_001367854.1:c.212G>T NP_001354783.1:p.Arg71Leu missense NM_001407044.1:c.1394G>T NP_001393973.1:p.Arg465Leu missense NM_001407045.1:c.1349G>T NP_001393974.1:p.Arg450Leu missense NM_001407046.1:c.1354+647G>T intron variant NM_001407047.1:c.1277G>T NP_001393976.1:p.Arg426Leu missense NM_001407048.1:c.1259G>T NP_001393977.1:p.Arg420Leu missense NM_001407049.1:c.1303+647G>T intron variant NM_001407050.1:c.1226G>T NP_001393979.1:p.Arg409Leu missense NM_001407051.1:c.638G>T NP_001393980.1:p.Arg213Leu missense NM_024424.5:c.1400G>T NP_077742.3:p.Arg467Leu missense NM_024425.2:c.1334G>T NP_077743.2:p.Arg445Leu missense NR_160306.1:n.1732G>T non-coding transcript variant NR_176266.1:n.1681G>T non-coding transcript variant NC_000011.10:g.32392019C>A NC_000011.9:g.32413565C>A NG_009272.1:g.48523G>T LRG_525:g.48523G>T LRG_525t1:c.1385G>T LRG_525p1:p.Arg462Leu LRG_525t2:c.749G>T LRG_525p2:p.Arg250Leu - Protein change
- R213L, R233L, R250L, R409L, R420L, R426L, R445L, R450L, R462L, R465L, R467L, R71L
- Other names
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- Canonical SPDI
- NC_000011.10:32392018:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| WT1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
914 | 1671 | |
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
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Tier I (Strong)
- prognostic
- poor outcome
(1)
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Jan 24, 2024 | RCV003883245.1 |
Submissions - Somatic
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Clinical impact
Help
The submitted somatic clinical impact for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Tier I (Strong)
- Prognostic
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poor outcome (Jan 24, 2024)
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no assertion criteria provided
Method: clinical testing
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Acute myeloid leukemia
Affected status: unknown
Allele origin:
somatic
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Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health
Accession: SCV004697533.1
First In ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
Comment:
This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. This variant is similar to … (more)
This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. This variant is similar to WT1 p.Arg467Pro, which also substitutes a non-polar amino acid for the charged polar Arg and was classified Pathogenic in ClinVar (VCV000003491.3). ClinVar accession VCV000419332.13 classifies WT1 p.Arg467Gln as Likely Pathogenic/Pathogenic. (less)
Clinical Features:
Bone marrow hypercellularity (present) , Granulocytic hyperplasia (present)
Age: 70-79 years
Sex: female
Tissue: peripheral blood with 5% CD34/CD117-positive myeloblasts
Comment on evidence:
The patient was treated with 5-azyctadine for hypercellular bone marrow with 5-9% blasts; however, five months later, a bone marrow biopsy showed 37% blasts positive … (more)
The patient was treated with 5-azyctadine for hypercellular bone marrow with 5-9% blasts; however, five months later, a bone marrow biopsy showed 37% blasts positive for CD33, CD34, CD117, and HLA-DR, consistent with AML, and a novel translocation t(4;7)(q12;q21.2). After induction chemotherapy with cytarabine and daunorubicin, a day-14 biopsy showed response to therapy. Following eight months of complete remission, the patient developed a relapse of AML. Flow cytometry of peripheral blood demonstrated 5% CD34/CD117-positive myeloblasts. The myeloid population displayed dysgranulopoiesis indicative of hypogranulation, and aberrant CD56 coexpression in a myelomonocytic subpopulation. Karyotype analysis detected the same t(4;7) translocation. Chromosome microarray testing indicated copy neutral loss of heterozygosity of 21q11.1qter and loss of a small segment in band 2p13.1 in 100% of the DNA from a blood sample. Blood RNA NGS analysis detected AKAP9::PDGFRA fusion transcripts consistent with the translocation. Additional somatic mutations were detected at AML relapse; a RUNX1 p.Arg162Lys variant was homozygous due to the LOH of 21q containing the RUNX1 locus at 21q22.12. Heterozygous somatic mutations of note were WT1 p.Arg462Leu (42% allele frequency), DNMT3A p.Arg882His (46%), and MYC p.Thr73Ala (47%). (less)
Method: Average 800x coverage of all exons from 275 cancer-related genes.
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Comment:
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Wilms Tumor 1 Mutations Are Independent Poor Prognostic Factors in Pediatric Acute Myeloid Leukemia. | Wang Y | Frontiers in oncology | 2021 | PMID: 33968731 |
| Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years. | Eisfeld AK | Leukemia | 2020 | PMID: 32461631 |
| WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. | Krauth MT | Leukemia | 2015 | PMID: 25110071 |
| WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. | Hou HA | Blood | 2010 | PMID: 20368469 |
| Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. | Renneville A | Cancer | 2009 | PMID: 19536888 |
| Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. | Hollink IH | Blood | 2009 | PMID: 19171881 |
| Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. | Virappane P | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18591546 |
| Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. | Paschka P | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18559874 |
Text-mined citations for this variant ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.