proposed classification - variant undergoing re-assessment, contact laboratory
ClinVar Genomic variation as it relates to human health
NM_024426.6(WT1):c.1447+5G>A
Germline
Classification
Help
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.
(22)
Help
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.
Pathogenic
22
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024426.6(WT1):c.1447+5G>A
Variation ID: 3493 Accession: VCV000003493.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 32391967 (GRCh38) [ NCBI UCSC ] 11: 32413513 (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 Oct 8, 2024 Mar 14, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024426.6:c.1447+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_000378.6:c.1387+14G>A intron variant NM_001198551.2:c.787+14G>A intron variant NM_001198552.2:c.745+5G>A intron variant NM_001367854.1:c.259+5G>A intron variant NM_001407044.1:c.1432+14G>A intron variant NM_001407045.1:c.1396+5G>A intron variant NM_001407046.1:c.1354+699G>A intron variant NM_001407047.1:c.1315+14G>A intron variant NM_001407048.1:c.1306+5G>A intron variant NM_001407049.1:c.1303+699G>A intron variant NM_001407050.1:c.1273+5G>A intron variant NM_001407051.1:c.685+5G>A intron variant NM_024424.5:c.1438+14G>A intron variant NC_000011.10:g.32391967C>T NC_000011.9:g.32413513C>T NG_009272.1:g.48575G>A LRG_525:g.48575G>A - Protein change
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- Other names
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splice site
1432+5G>A
IVS9+5G>A
IVS9DS, G-A, +5
- Canonical SPDI
- NC_000011.10:32391966: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
Help
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 | ||
|---|---|---|---|---|---|---|
| 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 - Germline
| Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2022 | RCV000003665.6 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000030876.11 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2015 | RCV000208283.2 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2024 | RCV000589623.9 | |
| Pathogenic (1) |
criteria provided, single submitter
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Mar 13, 2023 | RCV000705142.8 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 24, 2023 | RCV001288155.13 | |
| Pathogenic (2) |
criteria provided, single submitter
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Feb 2, 2023 | RCV001290018.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Feb 19, 2022 | RCV002482822.1 | |
| Pathogenic (1) |
no assertion criteria provided
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Feb 9, 2024 | RCV004547457.2 |
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
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 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 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Frasier syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731767.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 06, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Pathogenic
(Oct 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020923.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 13, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000834127.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 9 (PMID: 1302008, 9499425). ClinVar contains an entry for this variant (Variation ID: 3493). This variant is also known as IVS9+5G>A and c.1228+5G>A. This variant has been observed in individual(s) with Frasier syndrome and/or steroid-resistant nephrotic syndrome (PMID: 9499425, 20442690, 25818337, 27719739). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the WT1 gene. It does not directly change the encoded amino acid sequence of the WT1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. (less)
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Frasier syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086640.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) (GeneReviews); and Wilms tumor, type 1 (MIM#194070), respectively. (I) 0107 - This gene is associated with autosomal dominant disease. It is noted that Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) represent a phenotypic continuum (ClinGen Expert Panel). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Minigene assay and RT-PCR of cDNA obtained from gonadal tissue of an affected individual demonstrated aberrant splicing, leading to a reduction in +KTS isoform (PMIDs: 1302008, 9499425). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals described as having Frasier syndrome and steroid-resistant nephrotic syndrome, type 4 , including de novo events (PMIDs: 16439601, 25623218; DECIPHER). It is also consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(May 24, 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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199006.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Nov 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Familial idiopathic steroid-resistant nephrotic syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264319.2
First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Drash syndrome
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000890902.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 14, 2019)
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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: SCV001475083.1
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 negatively affect a known splice site. Assessment of experimental evidence … (more)
Not found in the total gnomAD dataset, and the data is high quality. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. 3 de novo cases with parental identity not confirmed. (less)
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Pathogenic
(Jul 16, 2019)
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criteria provided, single submitter
Method: clinical testing
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Frasier syndrome
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001523310.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Nov 27, 2019)
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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: SCV001767447.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Published functional studies demonstrate a damaging effect: aberrant splicing resulting in disruption of the ratio of WT1 isoforms (Bruening 1992, Klamt 1998); Not observed in … (more)
Published functional studies demonstrate a damaging effect: aberrant splicing resulting in disruption of the ratio of WT1 isoforms (Bruening 1992, Klamt 1998); Not observed in large population cohorts (Lek 2016); Also known as c.1228+5G>A; This variant is associated with the following publications: (PMID: 32203225, 31447099, 7959750, 8281163, 1302008, 9499425, 30406062, 28780565, 28204945, 25818337, 20442690, 23515051, 10505700, 11354777) (less)
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Pathogenic
(Jan 27, 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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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002072597.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 09, 2020)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051463.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PS4, PP3, PM2
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Pathogenic
(Sep 01, 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: SCV002572949.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.83). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 23515051). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003493 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Nephrotic syndrome (present) , Failure to thrive (present) , Hypertensive disorder (present) , Distal renal tubular acidosis (present)
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Pathogenic
(Feb 19, 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: SCV002790670.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Nephrotic syndrome, type 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Study: Broad Institute Center for Mendelian Genomics (CMG)
Accession: SCV000693892.2 First in ClinVar: Mar 17, 2018 Last updated: May 06, 2023 |
Comment:
The heterozygous c.1432+5G>A variant in WT1 was identified by our study in one individual with steroid-resistant nephrotic syndrome. Trio exome analysis revealed this variant to … (more)
The heterozygous c.1432+5G>A variant in WT1 was identified by our study in one individual with steroid-resistant nephrotic syndrome. Trio exome analysis revealed this variant to be de novo. The c.1432+5G>A variant in WT1 has been reported in 19 unrelated individuals with WT1 disorder (PMID: 23295293, PMID: 27719739, PMID: 21499692, PMID: 22099579, PMID: 24856380, PMID: 10762296, PMID: 20442690, PMID: 9499425, PMID: 1302008). This variant was found to be de novo in 13 individuals with confirmed paternity and maternity (PMID: 28204945, PMID: 28780565, PMID: 23515051, PMID: 21499692, PMID: 17694336, PMID: 10762296, PMID: 9499425, PMID: 1302008). This variant is assumed de novo in 10 individuals, but maternity and paternity have not been confirmed (PMID: 23295293, PMID: 27719739, PMID: 28204945, PMID: 22099579, PMID: 24856380, PMID: 9499425). This variant has also been reported in ClinVar (Variation ID: 3493) and has been interpreted as pathogenic by multiple submitters. Multiple variants in the same region as the c.1432+5G>A variant have been reported in association with disease, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 9499425). This variant was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. RT-PCR analysis performed on affected tissue shows this variant results in altered splicing of WT1, leading to an altered ratio of the +/- KTS isoforms (PMID: 17694336, PMID: 9499425, PMID: 1302008). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant WT1 disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3_Moderate, PS4, PM1_Supporting, PM2_Supporting (Richards 2015). (less)
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Pathogenic
(Feb 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: SCV004041062.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Mar 14, 2024)
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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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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005088811.2
First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024 |
Comment:
This variant lies in the splice donor site, in intron 9 of the WT1 gene. In silico splice prediction tools (ASSP and NNSPLICE) predicted this … (more)
This variant lies in the splice donor site, in intron 9 of the WT1 gene. In silico splice prediction tools (ASSP and NNSPLICE) predicted this variant to interfere with splicing. The variant (also known as 1228+5G>A and IVS9+5G>A) has been reported in the in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome [PMID: 23515051, 1302008, 20442690]. In vitro functional studies indicate that this variant results in defective splicing resulting in disruption of the ratio of WT1 isoforms [PMID: 9499425]. (less)
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Pathogenic
(Apr 01, 1998)
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no assertion criteria provided
Method: literature only
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FRASIER SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023839.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Klamt et al. (1998) described 6 cases of an IVS9DS+5G-A mutation in the WT1 gene in patients with Frasier syndrome (136680). Merging of mutational data … (more)
Klamt et al. (1998) described 6 cases of an IVS9DS+5G-A mutation in the WT1 gene in patients with Frasier syndrome (136680). Merging of mutational data from 18 cases demonstrated a striking bias: 15 of the 18 cases showed either the +4C-T (607102.0018) or the +5G-A mutations. This mutation hotspot probably results from the potential to deaminate 5-methylcytosine at the +4/+5 CpG dinucleotide. Klamt et al. (1998) showed that disruption of alternative splicing at the exon 9 donor splice site prevents synthesis of the usually more abundant WT1(+KTS) isoform from the mutant allele. In contrast to Denys-Drash syndrome (194080), no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo, as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have different functions, and the pathology of Frasier syndrome suggests that gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform. (The +KTS isoform has 3 additional amino acids, lys-thr-ser, between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991).) (less)
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Pathogenic
(May 01, 1992)
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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: SCV000023828.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with Denys-Drash syndrome (194080), with renal failure due to glomerular sclerosis associated with female external genitalia and a 46,XY karyotype, Bruening et … (more)
In a patient with Denys-Drash syndrome (194080), with renal failure due to glomerular sclerosis associated with female external genitalia and a 46,XY karyotype, Bruening et al. (1992) identified a G-to-A transition at position +5 of the splice donor site within intron 9. It appeared that the mutation affected the alternative splice site selection at exon 9. (less)
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Pathogenic
(Feb 09, 2024)
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no assertion criteria provided
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: SCV004119771.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The WT1 c.1432+5G>A variant is predicted to interfere with splicing. This variant was reported in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome (Lipska … (more)
The WT1 c.1432+5G>A variant is predicted to interfere with splicing. This variant was reported in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome (Lipska et al. 2013. PubMed ID: 23515051; Bruening et al. 1992. PubMed ID: 1302008, reported as 1228+5G>A; Li et al. 2010. PubMed ID: 20442690, reported as IVS9+5G>A). In vitro functional studies indicate that this variant results in defective splicing (Klamt et al. 1998. PubMed ID: 9499425). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(May 17, 2018)
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no assertion criteria provided
Method: clinical testing
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Nephrotic syndrome, type 4
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000863865.1
First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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not provided
(-)
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no classification provided
Method: literature only
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Wilms tumor 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001478075.2
First in ClinVar: Jan 26, 2021 Last updated: Oct 01, 2022 |
Comment:
Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis
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Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 9 (PMID: 1302008, 9499425). ClinVar contains an entry for this variant (Variation ID: 3493). This variant is also known as IVS9+5G>A and c.1228+5G>A. This variant has been observed in individual(s) with Frasier syndrome and/or steroid-resistant nephrotic syndrome (PMID: 9499425, 20442690, 25818337, 27719739). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the WT1 gene. It does not directly change the encoded amino acid sequence of the WT1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) (GeneReviews); and Wilms tumor, type 1 (MIM#194070), respectively. (I) 0107 - This gene is associated with autosomal dominant disease. It is noted that Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) represent a phenotypic continuum (ClinGen Expert Panel). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Minigene assay and RT-PCR of cDNA obtained from gonadal tissue of an affected individual demonstrated aberrant splicing, leading to a reduction in +KTS isoform (PMIDs: 1302008, 9499425). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals described as having Frasier syndrome and steroid-resistant nephrotic syndrome, type 4 , including de novo events (PMIDs: 16439601, 25623218; DECIPHER). It is also consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. 3 de novo cases with parental identity not confirmed.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Published functional studies demonstrate a damaging effect: aberrant splicing resulting in disruption of the ratio of WT1 isoforms (Bruening 1992, Klamt 1998); Not observed in large population cohorts (Lek 2016); Also known as c.1228+5G>A; This variant is associated with the following publications: (PMID: 32203225, 31447099, 7959750, 8281163, 1302008, 9499425, 30406062, 28780565, 28204945, 25818337, 20442690, 23515051, 10505700, 11354777)
Comment:
PS3, PS4, PP3, PM2
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.83). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 23515051). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003493 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The heterozygous c.1432+5G>A variant in WT1 was identified by our study in one individual with steroid-resistant nephrotic syndrome. Trio exome analysis revealed this variant to be de novo. The c.1432+5G>A variant in WT1 has been reported in 19 unrelated individuals with WT1 disorder (PMID: 23295293, PMID: 27719739, PMID: 21499692, PMID: 22099579, PMID: 24856380, PMID: 10762296, PMID: 20442690, PMID: 9499425, PMID: 1302008). This variant was found to be de novo in 13 individuals with confirmed paternity and maternity (PMID: 28204945, PMID: 28780565, PMID: 23515051, PMID: 21499692, PMID: 17694336, PMID: 10762296, PMID: 9499425, PMID: 1302008). This variant is assumed de novo in 10 individuals, but maternity and paternity have not been confirmed (PMID: 23295293, PMID: 27719739, PMID: 28204945, PMID: 22099579, PMID: 24856380, PMID: 9499425). This variant has also been reported in ClinVar (Variation ID: 3493) and has been interpreted as pathogenic by multiple submitters. Multiple variants in the same region as the c.1432+5G>A variant have been reported in association with disease, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 9499425). This variant was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. RT-PCR analysis performed on affected tissue shows this variant results in altered splicing of WT1, leading to an altered ratio of the +/- KTS isoforms (PMID: 17694336, PMID: 9499425, PMID: 1302008). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant WT1 disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3_Moderate, PS4, PM1_Supporting, PM2_Supporting (Richards 2015).
Comment:
This variant lies in the splice donor site, in intron 9 of the WT1 gene. In silico splice prediction tools (ASSP and NNSPLICE) predicted this variant to interfere with splicing. The variant (also known as 1228+5G>A and IVS9+5G>A) has been reported in the in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome [PMID: 23515051, 1302008, 20442690]. In vitro functional studies indicate that this variant results in defective splicing resulting in disruption of the ratio of WT1 isoforms [PMID: 9499425].
Comment:
The WT1 c.1432+5G>A variant is predicted to interfere with splicing. This variant was reported in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome (Lipska et al. 2013. PubMed ID: 23515051; Bruening et al. 1992. PubMed ID: 1302008, reported as 1228+5G>A; Li et al. 2010. PubMed ID: 20442690, reported as IVS9+5G>A). In vitro functional studies indicate that this variant results in defective splicing (Klamt et al. 1998. PubMed ID: 9499425). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis
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. |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 9 (PMID: 1302008, 9499425). ClinVar contains an entry for this variant (Variation ID: 3493). This variant is also known as IVS9+5G>A and c.1228+5G>A. This variant has been observed in individual(s) with Frasier syndrome and/or steroid-resistant nephrotic syndrome (PMID: 9499425, 20442690, 25818337, 27719739). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the WT1 gene. It does not directly change the encoded amino acid sequence of the WT1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) (GeneReviews); and Wilms tumor, type 1 (MIM#194070), respectively. (I) 0107 - This gene is associated with autosomal dominant disease. It is noted that Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) represent a phenotypic continuum (ClinGen Expert Panel). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Minigene assay and RT-PCR of cDNA obtained from gonadal tissue of an affected individual demonstrated aberrant splicing, leading to a reduction in +KTS isoform (PMIDs: 1302008, 9499425). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals described as having Frasier syndrome and steroid-resistant nephrotic syndrome, type 4 , including de novo events (PMIDs: 16439601, 25623218; DECIPHER). It is also consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. 3 de novo cases with parental identity not confirmed.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Published functional studies demonstrate a damaging effect: aberrant splicing resulting in disruption of the ratio of WT1 isoforms (Bruening 1992, Klamt 1998); Not observed in large population cohorts (Lek 2016); Also known as c.1228+5G>A; This variant is associated with the following publications: (PMID: 32203225, 31447099, 7959750, 8281163, 1302008, 9499425, 30406062, 28780565, 28204945, 25818337, 20442690, 23515051, 10505700, 11354777)
Comment:
PS3, PS4, PP3, PM2
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.83). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 23515051). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003493 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The heterozygous c.1432+5G>A variant in WT1 was identified by our study in one individual with steroid-resistant nephrotic syndrome. Trio exome analysis revealed this variant to be de novo. The c.1432+5G>A variant in WT1 has been reported in 19 unrelated individuals with WT1 disorder (PMID: 23295293, PMID: 27719739, PMID: 21499692, PMID: 22099579, PMID: 24856380, PMID: 10762296, PMID: 20442690, PMID: 9499425, PMID: 1302008). This variant was found to be de novo in 13 individuals with confirmed paternity and maternity (PMID: 28204945, PMID: 28780565, PMID: 23515051, PMID: 21499692, PMID: 17694336, PMID: 10762296, PMID: 9499425, PMID: 1302008). This variant is assumed de novo in 10 individuals, but maternity and paternity have not been confirmed (PMID: 23295293, PMID: 27719739, PMID: 28204945, PMID: 22099579, PMID: 24856380, PMID: 9499425). This variant has also been reported in ClinVar (Variation ID: 3493) and has been interpreted as pathogenic by multiple submitters. Multiple variants in the same region as the c.1432+5G>A variant have been reported in association with disease, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 9499425). This variant was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. RT-PCR analysis performed on affected tissue shows this variant results in altered splicing of WT1, leading to an altered ratio of the +/- KTS isoforms (PMID: 17694336, PMID: 9499425, PMID: 1302008). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant WT1 disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3_Moderate, PS4, PM1_Supporting, PM2_Supporting (Richards 2015).
Comment:
This variant lies in the splice donor site, in intron 9 of the WT1 gene. In silico splice prediction tools (ASSP and NNSPLICE) predicted this variant to interfere with splicing. The variant (also known as 1228+5G>A and IVS9+5G>A) has been reported in the in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome [PMID: 23515051, 1302008, 20442690]. In vitro functional studies indicate that this variant results in defective splicing resulting in disruption of the ratio of WT1 isoforms [PMID: 9499425].
Comment:
The WT1 c.1432+5G>A variant is predicted to interfere with splicing. This variant was reported in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome (Lipska et al. 2013. PubMed ID: 23515051; Bruening et al. 1992. PubMed ID: 1302008, reported as 1228+5G>A; Li et al. 2010. PubMed ID: 20442690, reported as IVS9+5G>A). In vitro functional studies indicate that this variant results in defective splicing (Klamt et al. 1998. PubMed ID: 9499425). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data. | Hardcastle A | American journal of medical genetics. Part A | 2022 | PMID: 35904974 |
| Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population. | Varner JD | Frontiers in pediatrics | 2018 | PMID: 30406062 |
| 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 |
| Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. | Wang F | Pediatric nephrology (Berlin, Germany) | 2017 | PMID: 28204945 |
| Early recognition of gonadal dysgenesis in congenital nephrotic syndrome . | Ukarapong S | Clinical nephrology | 2016 | PMID: 27719739 |
| 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 |
| Gonadal tumor in Frasier syndrome: a review and classification. | Ezaki J | Cancer prevention research (Philadelphia, Pa.) | 2015 | PMID: 25623218 |
| Retrospective mutational analysis of NPHS1, NPHS2, WT1 and LAMB2 in children with steroid-resistant focal segmental glomerulosclerosis - a single-centre experience. | Bińczak-Kuleta A | Bosnian journal of basic medical sciences | 2014 | PMID: 24856380 |
| Genetic screening in adolescents with steroid-resistant nephrotic syndrome. | Lipska BS | Kidney international | 2013 | PMID: 23515051 |
| Frasier syndrome: four new cases with unusual presentations. | Guaragna MS | Arquivos brasileiros de endocrinologia e metabologia | 2012 | PMID: 23295293 |
| 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 |
| WT1 gene mutations in Chinese children with early onset nephrotic syndrome. | Li J | Pediatric research | 2010 | PMID: 20442690 |
| WT1 mutation and podocyte molecular expression in a Chinese Frasier syndrome patient. | Li J | Pediatric nephrology (Berlin, Germany) | 2007 | PMID: 17694336 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. | Mucha B | Pediatric research | 2006 | PMID: 16439601 |
| Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy? | Koziell A | Clinical endocrinology | 2000 | PMID: 10762296 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. | Klamt B | Human molecular genetics | 1998 | PMID: 9499425 |
| Donor splice-site mutations in WT1 are responsible for Frasier syndrome. | Barbaux S | Nature genetics | 1997 | PMID: 9398852 |
| Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development. | Bruening W | Nature genetics | 1992 | PMID: 1302008 |
| Alternative splicing and genomic structure of the Wilms tumor gene WT1. | Haber DA | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 1658787 |
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Text-mined citations for rs587776576 ...
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Record last updated Oct 27, 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.