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

dbSNP: rs587776576

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208283	SCV000264319	pathogenic	Familial idiopathic steroid-resistant nephrotic syndrome	2015-11-02	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000589623	SCV000693892	pathogenic	Nephrotic syndrome, type 4	2023-05-02	criteria provided, single submitter	curation	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).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030876	SCV000731767	pathogenic	Frasier syndrome	2020-01-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705142	SCV000834127	pathogenic	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2023-03-13	criteria provided, single submitter	clinical testing	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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000003665	SCV000890902	pathogenic	Drash syndrome	2018-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001288155	SCV001475083	pathogenic	not provided	2019-10-14	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000030876	SCV001523310	pathogenic	Frasier syndrome	2019-07-16	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001288155	SCV001767447	pathogenic	not provided	2019-11-27	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV001288155	SCV002020923	pathogenic	not provided	2021-10-21	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001288155	SCV002051463	pathogenic	not provided	2020-11-09	criteria provided, single submitter	clinical testing	PS3, PS4, PP3, PM2
Daryl Scott Lab, Baylor College of Medicine	RCV000003665	SCV002072597	pathogenic	Drash syndrome	2022-01-27	criteria provided, single submitter	clinical testing
3billion	RCV000589623	SCV002572949	pathogenic	Nephrotic syndrome, type 4	2022-09-01	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002482822	SCV002790670	pathogenic	Aniridia 1; Drash syndrome; Frasier syndrome; Meacham syndrome; Mesothelioma, malignant; Nephrotic syndrome, type 4; Wilms tumor 1; 11p partial monosomy syndrome	2022-02-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001290018	SCV004041062	pathogenic	Wilms tumor 1	2023-02-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000030876	SCV005086640	pathogenic	Frasier syndrome	2023-07-17	criteria provided, single submitter	clinical testing	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
Breakthrough Genomics, Breakthrough Genomics	RCV000589623	SCV005088811	pathogenic	Nephrotic syndrome, type 4	2024-03-14	criteria provided, single submitter	clinical testing	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].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001288155	SCV005199006	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing
OMIM	RCV000003665	SCV000023828	pathogenic	Drash syndrome	1992-05-01	no assertion criteria provided	literature only
OMIM	RCV000030876	SCV000023839	pathogenic	Frasier syndrome	1998-04-01	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000589623	SCV000863865	pathogenic	Nephrotic syndrome, type 4	2018-05-17	no assertion criteria provided	clinical testing
GeneReviews	RCV001290018	SCV001478075	not provided	Wilms tumor 1		no assertion provided	literature only	Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis
PreventionGenetics, part of Exact Sciences	RCV004547457	SCV004119771	pathogenic	WT1-related disorder	2024-02-09	no assertion criteria provided	clinical testing	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.