ClinVar Genomic variation as it relates to human health
NM_024426.6(WT1):c.1405G>A (p.Asp469Asn)
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.1405G>A (p.Asp469Asn)
Variation ID: 3490 Accession: VCV000003490.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 32392014 (GRCh38) [ NCBI UCSC ] 11: 32413560 (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 Oct 21, 2016 Aug 26, 2023 Aug 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024426.6:c.1405G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077744.4:p.Asp469Asn missense NM_000378.6:c.1354G>A NP_000369.4:p.Asp452Asn missense NM_001198551.2:c.754G>A NP_001185480.1:p.Asp252Asn missense NM_001198552.2:c.703G>A NP_001185481.1:p.Asp235Asn missense NM_001367854.1:c.217G>A NP_001354783.1:p.Asp73Asn missense NM_001407044.1:c.1399G>A NP_001393973.1:p.Asp467Asn missense NM_001407045.1:c.1354G>A NP_001393974.1:p.Asp452Asn missense NM_001407047.1:c.1282G>A NP_001393976.1:p.Asp428Asn missense NM_001407048.1:c.1264G>A NP_001393977.1:p.Asp422Asn missense NM_001407050.1:c.1231G>A NP_001393979.1:p.Asp411Asn missense NM_001407051.1:c.643G>A NP_001393980.1:p.Asp215Asn missense NM_024424.5:c.1405G>A NP_077742.3:p.Asp469Asn missense NM_024425.2:c.1339G>A NP_077743.2:p.Asp447Asn missense NM_024426.4:c.1390G>A NR_160306.1:n.1737G>A non-coding transcript variant NR_176266.1:n.1686G>A NC_000011.10:g.32392014C>T NC_000011.9:g.32413560C>T NG_009272.1:g.48528G>A LRG_525:g.48528G>A LRG_525t1:c.1390G>A LRG_525p1:p.Asp464Asn LRG_525t2:c.754G>A LRG_525p2:p.Asp252Asn - Protein change
- D252N, D452N, D469N, D235N, D73N, D215N, D428N, D411N, D422N, D467N
- Other names
- D396N
- Canonical SPDI
- NC_000011.10:32392013: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
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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
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 (1) |
no assertion criteria provided
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Apr 1, 1998 | RCV000003661.4 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 3, 2022 | RCV000003662.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003322746.1 |
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
Help
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 03, 2022)
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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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3billion
Accession: SCV002058235.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 9529364, PS2_S). Same nucleotide change resulting in same amino acid … (more)
The variant has been previously reported as de novo in a similarly affected individual (PMID: 9529364, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with WT1 related disorder (ClinVar ID: VCV000003490, PMID:1655284). A different missense change at the same codon (p.Asp469Gly, p.Asp469Tyr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003489,VCV000547167, PMID:22876585, PMID:1655284, PMID:10738002, PMID:24402088, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.895, PP3_P). A missense variant is a common mechanism associated with Nephrotic syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Stage 5 chronic kidney disease (present) , Proteinuria (present)
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Pathogenic
(Aug 15, 2023)
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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: SCV004028420.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: decreased DNA binding affinity (Pelletier et al, 1991); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate a damaging effect: decreased DNA binding affinity (Pelletier et al, 1991); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.754G>A p.D252N, c.1186G>A p.D396N, and c.1405G>A p.D469N; This variant is associated with the following publications: (PMID: 24379226, 31816618, 1338906, 1655284, 25818337, 29869118, 29294058, 9529364, 9090524, 32891756, 32053599, 34031707, 31328266, 33392118, 25077094, 20442690, Bekheirnia2021[article], 15665984) (less)
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Pathogenic
(Apr 01, 1998)
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no assertion criteria provided
Method: literature only
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NEPHROTIC SYNDROME, TYPE 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023825.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2016 |
Comment on evidence:
In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a 1186G-A transition in the WT1 gene, resulting in an asp396-to-asn (D396N) substitution. … (more)
In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a 1186G-A transition in the WT1 gene, resulting in an asp396-to-asn (D396N) substitution. Baird et al. (1992) and Little et al. (1993) identified the D396N mutation in patients with Denys-Drash syndrome. Wilms tumor tissue derived from the patient reported by Little et al. (1993) showed complete loss of WT1. In a 46,XX female with normal external genitalia and nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified heterozygosity for the 1186G-A transition in exon 9 of the WT1 gene, leading to the D396N substitution. (less)
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Pathogenic
(Apr 01, 1998)
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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: SCV000023824.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2016 |
Comment on evidence:
In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a 1186G-A transition in the WT1 gene, resulting in an asp396-to-asn (D396N) substitution. … (more)
In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a 1186G-A transition in the WT1 gene, resulting in an asp396-to-asn (D396N) substitution. Baird et al. (1992) and Little et al. (1993) identified the D396N mutation in patients with Denys-Drash syndrome. Wilms tumor tissue derived from the patient reported by Little et al. (1993) showed complete loss of WT1. In a 46,XX female with normal external genitalia and nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified heterozygosity for the 1186G-A transition in exon 9 of the WT1 gene, leading to the D396N substitution. (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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A novel WT1 gene mutation in a newborn infant diagnosed with Denys-Drash syndrome. | Hakan N | Genetic counseling (Geneva, Switzerland) | 2012 | PMID: 22876585 |
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 |
A clinical overview of WT1 gene mutations. | Little M | Human mutation | 1997 | PMID: 9090524 |
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 |
Text-mined citations for rs28941778 ...
HelpRecord last updated Aug 26, 2023
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.