VCV000003493.36 - ClinVar

NM_024426.6(WT1):c.1447+5G>A

Germline

Classification

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)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024426.6(WT1):c.1447+5G>A

Variation ID: 3493 Accession: VCV000003493.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p13 11: 32391967 (GRCh38) [ NCBI UCSC ] 11: 32413513 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

Other names

splice site
1432+5G>A
IVS9+5G>A
IVS9DS, G-A, +5

Canonical SPDI

NC_000011.10:32391966:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA016607 OMIM: 607102.0009 OMIM: 607102.0020 dbSNP: rs587776576 VarSome

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
Gene	OMIM	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.
WT1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	916	1675

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.
Drash syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 27, 2022	RCV000003665.6
Frasier syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000030876.11
Familial idiopathic steroid-resistant nephrotic syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 2, 2015	RCV000208283.2
Nephrotic syndrome, type 4	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000589623.9
11p partial monosomy syndrome Drash syndrome Frasier syndrome Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Mar 13, 2023	RCV000705142.8
Wilms tumor 1	Pathogenic (2)	criteria provided, single submitter	Feb 2, 2023	RCV001290018.4
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 24, 2023	RCV001288155.13
11p partial monosomy syndrome Aniridia 1 Drash syndrome Frasier syndrome Meacham syndrome Mesothelioma, malignant Nephrotic syndrome, type 4 Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Feb 19, 2022	RCV002482822.1
WT1-related disorder	Pathogenic (1)	no assertion criteria provided	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.
Pathogenic (Nov 02, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Familial idiopathic steroid-resistant nephrotic syndrome Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000264319.2 First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016	Publications: PubMed (4) PubMed: 1302008‚ 20442690‚ 23515051‚ 9499425 Number of individuals with the variant: 1
Pathogenic (Jan 10, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Frasier syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000731767.3 First in ClinVar: Apr 09, 2018 Last updated: Jul 06, 2020	Publications: PubMed (7) PubMed: 9499425‚ 25818337‚ 23515051‚ 24856380‚ 1302008‚ 23295293‚ 28204945 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 1
Pathogenic (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Drash syndrome Affected status: yes Allele origin: de novo	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002072597.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Publications: PubMed (1) PubMed: 35904974 Number of individuals with the variant: 1
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 4 Affected status: yes Allele origin: germline	3billion Accession: SCV002572949.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 23515051 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)
Pathogenic (Feb 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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	Fulgent Genetics, Fulgent Genetics Accession: SCV002790670.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020923.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199006.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 4 Affected status: yes Allele origin: germline	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)
Pathogenic (Feb 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Drash syndrome Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000890902.1 First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019	Publications: PubMed (4) PubMed: 9398852‚ 1302008‚ 9499425‚ 10762296 Number of individuals with the variant: 1
Pathogenic (Oct 14, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475083.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (13) PubMed: 1302008‚ 20442690‚ 9499425‚ 10762296‚ 28204945‚ 30406062‚ 28780565‚ 25818337‚ 23515051‚ 21499692‚ 17694336‚ 22099579‚ 24856380 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)
Pathogenic (Jul 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Frasier syndrome Affected status: yes Allele origin: de novo	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].
Pathogenic (Nov 27, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	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)
Pathogenic (Nov 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	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
Pathogenic (May 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Nephrotic syndrome, type 4 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	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	Publications: PubMed (1) PubMed: 9499425 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)
Pathogenic (Feb 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilms tumor 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041062.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Mar 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000834127.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 28492532‚ 17576681‚ 9536098‚ 1302008‚ 9499425‚ 20442690‚ 25818337‚ 27719739 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)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Frasier syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	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	Publications: PubMed (4) PubMed: 1302008‚ 9499425‚ 16439601‚ 25623218 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)
Pathogenic (May 01, 1992)	no assertion criteria provided Method: literature only	DENYS-DRASH SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023828.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 1302008 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)
Pathogenic (Apr 01, 1998)	no assertion criteria provided Method: literature only	FRASIER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023839.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 9499425‚ 1658787 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)
Pathogenic (Feb 09, 2024)	no assertion criteria provided Method: clinical testing	WT1-related condition Affected status: unknown Allele origin: germline	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)
Pathogenic (May 17, 2018)	no assertion criteria provided Method: clinical testing	Nephrotic syndrome, type 4 Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000863865.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
not provided (-)	no classification provided Method: literature only	Wilms tumor 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001478075.2 First in ClinVar: Jan 26, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 32352694‚ 9398852 BookShelf: NBK556455 BookShelf: NBK556455 Comment: Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis
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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:

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:

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:

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:

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:

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:

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.

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:

Citations for germline classification of this variant

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_024426.6(WT1):c.1447+5G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587776576 ...