ClinVar Genomic variation as it relates to human health
NM_024426.6(WT1):c.1400G>A (p.Arg467Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification 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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024426.6(WT1):c.1400G>A (p.Arg467Gln)
Variation ID: 419332 Accession: VCV000419332.15
- 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.
Germline Apr 27, 2017 Mar 16, 2024 Feb 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024426.6:c.1400G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077744.4:p.Arg467Gln missense NM_000378.6:c.1349G>A NP_000369.4:p.Arg450Gln missense NM_001198551.2:c.749G>A NP_001185480.1:p.Arg250Gln missense NM_001198552.2:c.698G>A NP_001185481.1:p.Arg233Gln missense NM_001367854.1:c.212G>A NP_001354783.1:p.Arg71Gln missense NM_001407044.1:c.1394G>A NP_001393973.1:p.Arg465Gln missense NM_001407045.1:c.1349G>A NP_001393974.1:p.Arg450Gln missense NM_001407047.1:c.1277G>A NP_001393976.1:p.Arg426Gln missense NM_001407048.1:c.1259G>A NP_001393977.1:p.Arg420Gln missense NM_001407050.1:c.1226G>A NP_001393979.1:p.Arg409Gln missense NM_001407051.1:c.638G>A NP_001393980.1:p.Arg213Gln missense NM_024424.5:c.1400G>A NP_077742.3:p.Arg467Gln missense NM_024425.2:c.1334G>A NP_077743.2:p.Arg445Gln missense NM_024426.2:c.1181G>A NR_160306.1:n.1732G>A non-coding transcript variant NR_176266.1:n.1681G>A NC_000011.10:g.32392019C>T NC_000011.9:g.32413565C>T NG_009272.1:g.48523G>A LRG_525:g.48523G>A LRG_525t1:c.1385G>A LRG_525p1:p.Arg462Gln LRG_525t2:c.749G>A LRG_525p2:p.Arg250Gln - Protein change
- R250Q, R467Q, R450Q, R71Q, R233Q, R213Q, R465Q, R409Q, R420Q, R445Q, R426Q
- Other names
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- Canonical SPDI
- NC_000011.10:32392018:C:T
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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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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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 |
896 | 1644 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2022 | RCV000484903.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 22, 2017 | RCV002294337.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2021 | RCV002506163.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2022 | RCV003458440.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 2, 2023 | RCV003147478.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2022 | RCV003225075.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2024 | RCV003766670.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2024 | RCV003915331.1 |
Submissions - Germline
Classification
Help
The submitted germline classification 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) |
Condition
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The condition 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
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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
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Aug 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Kidney disorder
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002587763.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
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Pathogenic
(Dec 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aniridia 1
Frasier syndrome Mesothelioma, malignant Wilms tumor 1 11p partial monosomy syndrome Drash syndrome Nephrotic syndrome, type 4 Meacham syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811610.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002817238.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant appears to occur de novo in literature and in an individual tested at Athena Diagnostics with clinical features associated with this gene (PMID: … (more)
This variant appears to occur de novo in literature and in an individual tested at Athena Diagnostics with clinical features associated with this gene (PMID: 21499692, 31937884). Additionally, it has been identified in multiple affected individuals (PMID: 16932893, 11322369, 1655284, 1338906, 21125408, 30963316, 9607189, 9475094). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 8810912). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Pathogenic
(Jun 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000567063.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals with Denys Drash syndrome, congenital nephrotic syndrome, or other urogenital abnormalities in the published literature and at GeneDx, including de novo observations … (more)
Observed in individuals with Denys Drash syndrome, congenital nephrotic syndrome, or other urogenital abnormalities in the published literature and at GeneDx, including de novo observations with confirmed parentage (Jeanpierre 1998, Schumacher 1998, Kohler 2011, Lehnhardt 2015, Weber 2016, Sen 2017, Brody 2019, Nishi 2019, Sun 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1181G>A (p.Arg394Gln); This variant is associated with the following publications: (PMID: 25818337, 9529364, 9607189, 21508141, 26248470, 28780565, 29474669, 30963316, 32891756, 29568099, 9745866, 29294058, 33726816, 32604935) (less)
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Pathogenic
(Feb 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Drash syndrome
Affected status: yes
Allele origin:
de novo
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921870.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. (I) 0107 - This gene is associated with autosomal … (more)
0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting <i>in silico</i> predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated putative nucleic acid binding site (NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg462Trp) variant has commonly been reported in individuals with Denys-Drash syndrome (PMIDs: 30963316, 25349199). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Denys-Drash syndrome or steroid-resistant nephrotic syndrome (PMIDs: 32891756, 30963316, 26248470, 25349199). It has also been reported as pathogenic in ClinVar. (SP) 1203 - This variant has been shown to be <i>de novo</i> in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Wilms tumor 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835196.2
First in ClinVar: Mar 11, 2023 Last updated: Oct 06, 2023 |
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Likely pathogenic
(Jun 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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WT1-related Wilms tumor
Affected status: unknown
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183394.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated
Geographic origin: Brazil
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Pathogenic
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Wilms tumor 1
Drash syndrome 11p partial monosomy syndrome Frasier syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004570761.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 462 of the WT1 protein (p.Arg462Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 462 of the WT1 protein (p.Arg462Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Denys-Drash syndrome and/or clinical features of WT1-related conditions (PMID: 9529364, 9745866, 21508141, 25818337, 26248470, 28780565, 29474669, 30963316, 32604935, 34490048). In at least one individual the variant was observed to be de novo. This variant is also known as p.R394Q and p.R467Q. ClinVar contains an entry for this variant (Variation ID: 419332). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg462 amino acid residue in WT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1327525, 1338906, 1655284, 9529364, 15509792, 17853480, 23715653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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WT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004733520.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The WT1 c.1385G>A variant is predicted to result in the amino acid substitution p.Arg462Gln. In the reported publications, this variant is listed as “p.R394Q”. This … (more)
The WT1 c.1385G>A variant is predicted to result in the amino acid substitution p.Arg462Gln. In the reported publications, this variant is listed as “p.R394Q”. This variant has previously been reported to be causative for Denys-Drash syndrome (Jeanpierre et al. 1998. PubMed ID: 9529364; Köhler et al. 2011. PubMed ID: 21508141; Lehnhardt et al. 2015. PubMed ID: 25818337). Other missense variants affecting the same amino acid (p.Arg462Gly, p.Arg462Trp, p.Arg462Pro, and p.Arg462Leu) have also been reported in association with nephrotic syndrome, Wilms tumor, and Denys-Drash syndrome (Chernin et al. 2010. PubMed ID: 20595692; Pelletier et al. 1991. PubMed ID: 1655284; Bruening et al. 1992. PubMed ID: 1302008; Royer-Pokora et al. 2004. PubMed ID: 15150775). This variant has not been reported in gnomAD, indicating it is rare. Based on the available evidence, we consider this variant to be pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical Utility of Rapid Exome Sequencing Combined With Mitochondrial DNA Sequencing in Critically Ill Pediatric Patients With Suspected Genetic Disorders. | Ouyang X | Frontiers in genetics | 2021 | PMID: 34490048 |
Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis. | Park E | Journal of clinical medicine | 2020 | PMID: 32604935 |
Detailed clinical manifestations at onset and prognosis of neonatal-onset Denys-Drash syndrome and congenital nephrotic syndrome of the Finnish type. | Nishi K | Clinical and experimental nephrology | 2019 | PMID: 30963316 |
Treatment and outcome of congenital nephrotic syndrome. | Bérody S | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2019 | PMID: 29474669 |
Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations. | Sen ES | Journal of medical genetics | 2017 | PMID: 28780565 |
Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing. | Weber S | Pediatric nephrology (Berlin, Germany) | 2016 | PMID: 26248470 |
Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1. | Lehnhardt A | Clinical journal of the American Society of Nephrology : CJASN | 2015 | PMID: 25818337 |
A familial WT1 mutation associated with incomplete Denys-Drash syndrome. | Zhu C | European journal of pediatrics | 2013 | PMID: 23715653 |
Analysis of the Wilms' tumor suppressor gene (WT1) in patients 46,XY disorders of sex development. | Köhler B | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21508141 |
WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. | Suri M | American journal of medical genetics. Part A | 2007 | PMID: 17853480 |
The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome. | Gao F | Molecular and cellular biology | 2004 | PMID: 15509792 |
In utero nephropathy, Denys-Drash syndrome and Potter phenotype. | Maalouf EF | Pediatric nephrology (Berlin, Germany) | 1998 | PMID: 9745866 |
Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. | Jeanpierre C | American journal of human genetics | 1998 | PMID: 9529364 |
Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. | Baird PN | Human molecular genetics | 1992 | PMID: 1338906 |
Inherited WT1 mutation in Denys-Drash syndrome. | Coppes MJ | Cancer research | 1992 | PMID: 1327525 |
Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. | Pelletier J | Cell | 1991 | PMID: 1655284 |
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Text-mined citations for rs121907903 ...
HelpRecord last updated May 12, 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.