ClinVar Genomic variation as it relates to human health
NM_024426.6(WT1):c.1316G>A (p.Arg439His)
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.1316G>A (p.Arg439His)
Variation ID: 3488 Accession: VCV000003488.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 32392704 (GRCh38) [ NCBI UCSC ] 11: 32414250 (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 4, 2013 Feb 28, 2024 Jan 17, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024426.6:c.1316G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077744.4:p.Arg439His missense NM_000378.6:c.1265G>A NP_000369.4:p.Arg422His missense NM_001198551.2:c.665G>A NP_001185480.1:p.Arg222His missense NM_001198552.2:c.614G>A NP_001185481.1:p.Arg205His missense NM_001367854.1:c.128G>A NP_001354783.1:p.Arg43His missense NM_001407044.1:c.1310G>A NP_001393973.1:p.Arg437His missense NM_001407045.1:c.1265G>A NP_001393974.1:p.Arg422His missense NM_001407046.1:c.1316G>A NP_001393975.1:p.Arg439His missense NM_001407047.1:c.1193G>A NP_001393976.1:p.Arg398His missense NM_001407049.1:c.1265G>A NP_001393978.1:p.Arg422His missense NM_001407050.1:c.1142G>A NP_001393979.1:p.Arg381His missense NM_001407051.1:c.554G>A NP_001393980.1:p.Arg185His missense NM_024424.5:c.1316G>A NP_077742.3:p.Arg439His missense NM_024425.2:c.1250G>A NP_077743.2:p.Arg417His missense NR_160306.1:n.1648G>A non-coding transcript variant NR_176266.1:n.1597G>A NC_000011.10:g.32392704C>T NC_000011.9:g.32414250C>T NG_009272.1:g.47838G>A LRG_525:g.47838G>A LRG_525t1:c.1301G>A LRG_525p1:p.Arg434His LRG_525t2:c.665G>A LRG_525p2:p.Arg222His - Protein change
- R222H, R422H, R439H, R205H, R43H, R398H, R437H, R185H, R381H
- Other names
- R366H
- Canonical SPDI
- NC_000011.10:32392703: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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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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
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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) |
no assertion criteria provided
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Jan 1, 2016 | RCV000003659.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2021 | RCV000484493.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 8, 2020 | RCV001250546.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 15, 2021 | RCV001851622.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2021 | RCV002243617.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 11, 2021 | RCV003147274.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2022 | RCV002496247.1 |
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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Pathogenic
(Jan 17, 2022)
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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: SCV002810914.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 15, 2021)
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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: SCV002231581.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg434 amino acid residue in WT1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg434 amino acid residue in WT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27300205, 9529364, 7795587, 22172722). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Denys-Drash syndrome and nephrotic syndrome (PMID: 1655284, 26882358, 30721404, 27719739, 30963316). This variant is also known as p.Arg366His in the literature. ClinVar contains an entry for this variant (Variation ID: 3488). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 434 of the WT1 protein (p.Arg434His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. (less)
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Pathogenic
(May 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Frasier syndrome
Wilms tumor 1 Drash syndrome Nephrotic syndrome, type 4
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425363.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Comment:
This WT1 variant has been reported in multiple individuals presenting with congenital nephrotic syndrome. A functional study has demonstrated that this variant is associated with … (more)
This WT1 variant has been reported in multiple individuals presenting with congenital nephrotic syndrome. A functional study has demonstrated that this variant is associated with a decrease in DNA binding affinity when compared to the wild-type protein. WT1 c.1301G>A is located within one of the four zinc finger regions that are important for protein function. This variant is absent from a large population dataset and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across all species assessed. We consider this variant to be pathogenic. (less)
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Pathogenic
(Jul 20, 2020)
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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 Inc
Accession: SCV001475081.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or … (more)
Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Results on protein functions were inconclusive. 2 de novo cases with parental identity not confirmed. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. (less)
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Pathogenic
(Oct 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 4
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512636.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong
Geographic origin: Brazil
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Pathogenic
(Dec 02, 2021)
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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: SCV000568577.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Identified in multiple individuals with Denys Drash syndrome as well as in patients with isolated diffuse mesangial sclerosis or early-onset nephrotic syndrome (Schumacher 1998, Pelletier … (more)
Identified in multiple individuals with Denys Drash syndrome as well as in patients with isolated diffuse mesangial sclerosis or early-onset nephrotic syndrome (Schumacher 1998, Pelletier 1991, Royer-Pokora 2004, Nishi 2019); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also reported as c.1097G>A (R366H); This variant is associated with the following publications: (PMID: 16479084, 26882358, 30963316, 15150775, 9607189, 1655284, 29294058, 1338906, 7645607, 9529364, 11322369, 16932893, 17853480, 15026863, 18203154, 26891727, 21434831, 24402088, 8810912, 27719739, 28780565, 30721404, 31937884, 32604935, 29474669) (less)
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Pathogenic
(Jun 11, 2021)
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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: SCV003835055.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Feb 15, 2008)
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no assertion criteria provided
Method: literature only
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DENYS-DRASH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023822.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a G-to-A transition in exon 8 of the WT1 gene, resulting in an … (more)
In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a G-to-A transition in exon 8 of the WT1 gene, resulting in an arg366-to-his (R366H) substitution in the second zinc finger domain. The same mutation was observed by Baird et al. (1992) in a patient with Denys-Drash syndrome. Antonius et al. (2008) reported another patient with Denys-Drash syndrome and a heterozygous R366H substitution. The authors stated that 10 DDS patients had been reported with this specific mutation, and noted that their patient was the third reported patient with DDS and congenital diaphragmatic hernia associated with the R366H mutation. A mutation in this same codon (R366C; 607102.0026) has been identified in a patient with Meacham syndrome (608978) and diaphragmatic hernia. (less)
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Pathogenic
(Jan 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Drash syndrome
Affected status: yes
Allele origin:
unknown
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Human Genetics Disease in Children – Taif University, Taif University
Accession: SCV000265969.1
First in ClinVar: Mar 16, 2016 Last updated: Mar 16, 2016 |
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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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Comprehensive genetic diagnosis of Japanese patients with severe proteinuria. | Nagano C | Scientific reports | 2020 | PMID: 31937884 |
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 |
Genetics of congenital and infantile nephrotic syndrome. | Sharief SN | World journal of pediatrics : WJP | 2019 | PMID: 30721404 |
Genotype-phenotype analysis of pediatric patients with WT1 glomerulopathy. | Ahn YH | Pediatric nephrology (Berlin, Germany) | 2017 | PMID: 27300205 |
Early recognition of gonadal dysgenesis in congenital nephrotic syndrome . | Ukarapong S | Clinical nephrology | 2016 | PMID: 27719739 |
Refining the Diagnosis of Congenital Nephrotic Syndrome on Long-term Stored Tissue: c.1097G>A (p.(Arg366His)) WT1 Mutation Causing Denys Drash Syndrome. | Hillen LM | Fetal and pediatric pathology | 2016 | PMID: 26882358 |
Genetic abnormalities and prognosis in patients with congenital and infantile nephrotic syndrome. | Cil O | Pediatric nephrology (Berlin, Germany) | 2015 | PMID: 25720465 |
WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. | Amin EM | Cancer cell | 2011 | PMID: 22172722 |
Genetic basis of congenital and infantile nephrotic syndromes. | Lee JH | American journal of kidney diseases : the official journal of the National Kidney Foundation | 2011 | PMID: 22099579 |
Broad and unexpected phenotypic expression in Greek children with steroid-resistant nephrotic syndrome due to mutations in the Wilms' tumor 1 (WT1) gene. | Megremis S | European journal of pediatrics | 2011 | PMID: 21499692 |
Novel mutations in steroid-resistant nephrotic syndrome diagnosed in Tunisian children. | Mbarek IB | Pediatric nephrology (Berlin, Germany) | 2011 | PMID: 21125408 |
Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G > A(Arg366His) mutation. | Antonius T | American journal of medical genetics. Part A | 2008 | PMID: 18203154 |
Hydrothorax in a patient with Denys-Drash syndrome associated with a diaphragmatic defect. | Cho HY | Pediatric nephrology (Berlin, Germany) | 2006 | PMID: 16932893 |
Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. | Royer-Pokora B | American journal of medical genetics. Part A | 2004 | PMID: 15150775 |
Pulmonary dysplasia, Denys-Drash syndrome and Wilms tumor 1 gene mutation in twins. | Dharnidharka VR | Pediatric nephrology (Berlin, Germany) | 2001 | PMID: 11322369 |
The human sex-determining gene SRY is a direct target of WT1. | Hossain A | The Journal of biological chemistry | 2001 | PMID: 11278460 |
Constitutional WT1 correlate with clinical features in children with progressive nephropathy. | Takata A | Journal of medical genetics | 2000 | PMID: 11182928 |
Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. | Schumacher V | Kidney international | 1998 | PMID: 9607189 |
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 |
Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome? | Kikuchi H | Journal of medical genetics | 1998 | PMID: 9475094 |
Effects of Denys-Drash syndrome point mutations on the DNA binding activity of the Wilms' tumor suppressor protein WT1. | Borel F | Biochemistry | 1996 | PMID: 8810912 |
DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. | Little M | Human molecular genetics | 1995 | PMID: 7795587 |
Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. | Baird PN | Human molecular genetics | 1992 | PMID: 1338906 |
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 rs121907901 ...
HelpRecord last updated Apr 06, 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.