VCV000003500.23 - ClinVar

NM_024426.6(WT1):c.1447+4C>T

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.

(16)

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/Likely 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+4C>T

Variation ID: 3500 Accession: VCV000003500.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p13 11: 32391968 (GRCh38) [ NCBI UCSC ] 11: 32413514 (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	Nov 24, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024426.6:c.1447+4C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000378.6:c.1387+13C>T		intron variant
NM_001198551.2:c.787+13C>T		intron variant
NM_001198552.2:c.745+4C>T		intron variant
NM_001367854.1:c.259+4C>T		intron variant
NM_001407044.1:c.1432+13C>T		intron variant
NM_001407045.1:c.1396+4C>T		intron variant
NM_001407046.1:c.1354+698C>T		intron variant
NM_001407047.1:c.1315+13C>T		intron variant
NM_001407048.1:c.1306+4C>T		intron variant
NM_001407049.1:c.1303+698C>T		intron variant
NM_001407050.1:c.1273+4C>T		intron variant
NM_001407051.1:c.685+4C>T		intron variant
NM_024424.5:c.1438+13C>T		intron variant
NC_000011.10:g.32391968G>A
NC_000011.9:g.32413514G>A
NG_009272.1:g.48574C>T
LRG_525:g.48574C>T

... more HGVS ... less HGVS

Protein change

Other names

1432+4C>T
IVS9+4C>T
IVS9DS, C-T, +4

Canonical SPDI

NC_000011.10:32391967:G:A

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: CA016600 OMIM: 607102.0018 dbSNP: rs587776577 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.
Nephrotic syndrome, type 4	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000003675.6
Frasier syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 9, 2024	RCV000003674.10
Familial idiopathic steroid-resistant nephrotic syndrome	Pathogenic (1)	no assertion criteria provided	Nov 27, 2014	RCV000157584.2
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 30, 2022	RCV000489749.4
Nephrotic range proteinuria	Likely pathogenic (1)	no assertion criteria provided	-	RCV001003818.2
Wilms tumor 1	Likely pathogenic (2)	criteria provided, single submitter	Dec 18, 2023	RCV001290017.5
11p partial monosomy syndrome Drash syndrome Frasier syndrome Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Feb 3, 2023	RCV001216104.7
WT1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2023	RCV004547458.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter 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 (Jan 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	WT1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004121402.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The WT1 c.1432+4C>T variant is predicted to interfere with splicing. This variant has been well documented to be pathogenic for Frasier syndrome and steroid-resistant nephrotic … (more) The WT1 c.1432+4C>T variant is predicted to interfere with splicing. This variant has been well documented to be pathogenic for Frasier syndrome and steroid-resistant nephrotic syndrome with FSGS (Barbaux et al. 1997. PubMed ID: 9398852; Melo et al. 2002. PubMed ID: 12050205; Li et al. 2010. PubMed ID: 20442690; Lipska et al. 2013. PubMed ID: 23515051). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
Likely Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilms tumor 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004842733.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (21) PubMed: 9398852‚ 9475094‚ 9499425‚ 9529364‚ 10094551‚ 10505699‚ 10561752‚ 10670748‚ 10792605‚ 11007843‚ 12050205‚ 20442690‚ 22908070‚ 23515051‚ 24161391‚ 25623218‚ 29668062‚ 30655312‚ 34622098‚ 35211794‚ 36980135 Comment: This variant substitutes a C nucleotide with a T nucleotide in the +4 position of the intron 9 splice donor site in the WT1 gene. … (more) This variant substitutes a C nucleotide with a T nucleotide in the +4 position of the intron 9 splice donor site in the WT1 gene. This variant is also known as c.1447+4C>T and IVS9+4C>T in the literature. RNA studies have found that this variant results in the increased splicing at an alternative donor site in exon 9, resulting in the deletion of the last nine nucleotides of exon 9 and the in-frame deletion of lysine (K), threonine (T) and serine (S) located in between zinc fingers 3 and 4 in the WT1 protein (PMID: 10792605, 34622098). Altered ratio between the two WT1 isoforms with and without the KTS motif are associated with Frasier syndrome (PMID: 9499425, 10561752). This variant has been reported in over 60 individuals affected with Frasier syndromes (PMID: 9398852, 9499425, 10094551, 10505699, 10670748, 10792605, 11007843, 12050205, 22908070, 25623218, 29668062, 34622098, 35211794, 36980135) and related clinical features (PMID: 9529364, 20442690, 23515051, 24161391, 30655312) and three individuals affected with Denys-Drash syndrome (PMID: 9475094). Among individuals diagnosed with Frasier syndrome at least one was affected with Wilms tumor and 19 individuals were affected with gonadal tumors (PMID: 10094551, 22908070, 25623218, 34622098). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Aug 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Frasier syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848204.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (7) PubMed: 9398852‚ 25813279‚ 23515051‚ 24161391‚ 22815844‚ 28204945‚ 20442690 Comment: The c.1432+4C>T variant in WT1 has been previously reported in >10 individuals with clinical features of Frasier syndrome, including in at 3 individuals with de … (more) The c.1432+4C>T variant in WT1 has been previously reported in >10 individuals with clinical features of Frasier syndrome, including in at 3 individuals with de novo occurrence (Barbaux 1997, Bastian 20115, Guaragna 2013, Hersmus 2012, Li 2010, Lispka 2013, Wang 2017) and segregated with disease in one affected family member. It was absent from large population studies and has been reported in ClinVar (Variation ID 3500). This variant is variant is located in the 5' splice region. Computational analyses and In vitro functional studies provide some evidence that the c.1432+4C>T variant may impact protein function (Barbaux 1997); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for Frasier syndrome in an autosomal dominant manner based upon de novo occurences, presence in affected individuals, absence from controls and functional evidence. ACMG/AMP Criteria applied: PM6_Strong, PP1_strong, PM2, PS3_supporting (Richards 2015). (less)
Pathogenic (Mar 31, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Frasier syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001430088.1 First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020	Sex: male Tissue: blood
Likely pathogenic (Feb 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 4 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512638.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PS4, PM2, PM6, PP1 Geographic origin: Brazil
Pathogenic (Dec 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577385.5 First in ClinVar: May 22, 2017 Last updated: Jan 07, 2023	Comment: Published functional studies demonstrate a damaging effect: abnormal gene splicing (Barbaux et al., 1997); Not observed in large population cohorts (gnomAD); In silico analysis supports … (more) Published functional studies demonstrate a damaging effect: abnormal gene splicing (Barbaux et al., 1997); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 1658787, 9398852, 22908070, 24856380, 17934764, 27300205, 34392242, 32838737, 31937884, 30348286, 24161391, 19484379, 21508141, 23515051, 20442690, 22815844, 9529364, 25905393, 10792605, 10670748, 9475094, 12050205, 25818337, 26668027, 16439601, 16780544, 10094551, 9499425, 25813279, 28204945, 28921387, 28476686, 29869118, 29668062, 30655312, 32581362, 32887937, 32381729, 32604935) (less)
Likely pathogenic (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 4 Affected status: yes Allele origin: de novo	Precision Medicine Center, Zhengzhou University Accession: SCV004218499.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024	Publications: PubMed (2) PubMed: 23302619‚ 25741868 Comment: PS2,PM2_p,PP3 Sex: male
Pathogenic (Feb 03, 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: SCV001387881.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 9398852‚ 9499425‚ 29668062‚ 17576681‚ 9536098‚ 12050205 Comment: 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. … (more) 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with WT1-related disorders (PMID: 9398852, 9499425, 29668062). In at least one individual the variant was observed to be de novo. This variant is also known as IVS9+4C>T. ClinVar contains an entry for this variant (Variation ID: 3500). 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 exon 9 (PMID: 9398852, 12050205). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005042851.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: The splice site donor variant c.1447+4C>T in the WT1 gene has been observed in individuals with WT1-related disorders Gomes et al., 2018. Studies have shown … (more) The splice site donor variant c.1447+4C>T in the WT1 gene has been observed in individuals with WT1-related disorders Gomes et al., 2018. Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 Buratti et al., 2007. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This splice variant in intron 9 affects the position of four nucleotides downstream of exon 9. It is submitted to ClinVar as Pathogenic multiple submissions. For these reasons, this variant has been classified as Pathogenic (less) Clinical Features: Abnormality of the kidney (present)
Pathogenic (Oct 09, 2024)	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: SCV005400451.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 9398852‚ 12050205‚ 30655312‚ 32352694 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease in this gene and is associated with Denys-Drash syndrome (MIM#194080); Frasier syndrome (MIM#136680); Meacham syndrome (MIM#608978) and Nephrotic syndrome, type 4 (MIM#256370) (PMID: 32352694). Loss of function is a known mechanism of disease in this gene and is associated with Wilms tumour, type 1 (MIM#194070). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of total RNA obtained from patients' samples indicated an increase in KTS- transcripts. This is suggestive of an increased use of an alternative splice site, which results in the loss of three amino acids (PMID: 9398852, 12050205). (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. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed as a de novo or inherited variant in multiple individuals with Frasier syndrome (PMID: 9398852, 12050205, 30655312). (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 (Jun 01, 2002)	no assertion criteria provided Method: literature only	FRASIER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023837.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (6) PubMed: 1658787‚ 9398852‚ 9499425‚ 10094551‚ 12050205‚ 9529364 Comment on evidence: Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows … (more) Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of 3 amino acids (lys-thr-ser, or KTS) between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991). In 3 unrelated patients with Frasier syndrome (136680), Barbaux et al. (1997) identified a mutation in the donor splice site in intron 9 of WT1, with the predicted loss of the so-called +KTS isoform. Examination of WT1 transcripts showed a diminution of the +KTS/-KTS isoform ratio in patients with Frasier syndrome. Two of 3 patients were found to carry a C-to-T transition at position +4 of intron 9 in 1 allele (IVSDS+4C-T). This nucleotide substitution was not detected in the DNA from either parent, indicating a de novo mutation. A third patient was found to have a mutation in intron 9 at position +6, substituting a thymidine for an adenine (IVS9DS+6A-T; 607102.0019). A screen of the SRY gene (480000) had failed to detect mutations in any of the 3 patients. Klamt et al. (1998) reported 3 cases of Frasier syndrome and the IVS9DS+4C-T mutation. Barbosa et al. (1999) stated that 18 patients with Frasier syndrome had been described, all with heterozygous point mutations affecting the donor splice site of intron 9 of WT1; none had presented with Wilms tumor. They described 2 patients with Frasier syndrome and the IVS9DS+4C-T mutation; one of these patients also had Wilms tumor. The mutation was detected in both peripheral blood and in tumor-derived DNA of the patient with Frasier syndrome and Wilms tumor. The congenital anomalies in these 2 patients were the same as in other cases of Frasier syndrome: female external genitalia, in spite of a 46,XY karyotype, and streak gonads. The nephroblastoma in the patient with Wilms tumor had been diagnosed at the age of 3 years. The possibility that the patient actually represented a case of Denys-Drash syndrome was rejected because of normal histology of the kidney removed at age 3; the late onset of proteinuria; the slow progression of nephropathy, once developed; and the presence of a complete female phenotype with dysgenetic gonads, typical of Frasier syndrome. Thus this is the only one of 20 patients carrying mutations within splice site 2 of exon 9 of the WT1 gene who developed Wilms tumor in association with the features of Frasier syndrome. Melo et al. (2002) reported a 19-year-old male with Frasier syndrome who had the IVS9+4C-T mutation, which predicts a change in splice site utilization. He had an unusual phenotype. WT1 transcript analysis showed reversal of the normal positive/negative KTS isoform ratio, confirming the diagnosis of FS. The authors concluded that this patient had the external genitalia characteristic of Denys-Drash syndrome, suggesting that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene. In a 46,XX female with nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified the IVS9+4C-T mutation in the WT1 gene. (less)
Pathogenic (Jun 01, 2002)	no assertion criteria provided Method: literature only	NEPHROTIC SYNDROME, TYPE 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023838.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (6) PubMed: 1658787‚ 9398852‚ 9499425‚ 10094551‚ 12050205‚ 9529364 Comment on evidence: Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows … (more) Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of 3 amino acids (lys-thr-ser, or KTS) between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991). In 3 unrelated patients with Frasier syndrome (136680), Barbaux et al. (1997) identified a mutation in the donor splice site in intron 9 of WT1, with the predicted loss of the so-called +KTS isoform. Examination of WT1 transcripts showed a diminution of the +KTS/-KTS isoform ratio in patients with Frasier syndrome. Two of 3 patients were found to carry a C-to-T transition at position +4 of intron 9 in 1 allele (IVSDS+4C-T). This nucleotide substitution was not detected in the DNA from either parent, indicating a de novo mutation. A third patient was found to have a mutation in intron 9 at position +6, substituting a thymidine for an adenine (IVS9DS+6A-T; 607102.0019). A screen of the SRY gene (480000) had failed to detect mutations in any of the 3 patients. Klamt et al. (1998) reported 3 cases of Frasier syndrome and the IVS9DS+4C-T mutation. Barbosa et al. (1999) stated that 18 patients with Frasier syndrome had been described, all with heterozygous point mutations affecting the donor splice site of intron 9 of WT1; none had presented with Wilms tumor. They described 2 patients with Frasier syndrome and the IVS9DS+4C-T mutation; one of these patients also had Wilms tumor. The mutation was detected in both peripheral blood and in tumor-derived DNA of the patient with Frasier syndrome and Wilms tumor. The congenital anomalies in these 2 patients were the same as in other cases of Frasier syndrome: female external genitalia, in spite of a 46,XY karyotype, and streak gonads. The nephroblastoma in the patient with Wilms tumor had been diagnosed at the age of 3 years. The possibility that the patient actually represented a case of Denys-Drash syndrome was rejected because of normal histology of the kidney removed at age 3; the late onset of proteinuria; the slow progression of nephropathy, once developed; and the presence of a complete female phenotype with dysgenetic gonads, typical of Frasier syndrome. Thus this is the only one of 20 patients carrying mutations within splice site 2 of exon 9 of the WT1 gene who developed Wilms tumor in association with the features of Frasier syndrome. Melo et al. (2002) reported a 19-year-old male with Frasier syndrome who had the IVS9+4C-T mutation, which predicts a change in splice site utilization. He had an unusual phenotype. WT1 transcript analysis showed reversal of the normal positive/negative KTS isoform ratio, confirming the diagnosis of FS. The authors concluded that this patient had the external genitalia characteristic of Denys-Drash syndrome, suggesting that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene. In a 46,XX female with nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified the IVS9+4C-T mutation in the WT1 gene. (less)
Pathogenic (Nov 27, 2014)	no assertion criteria provided Method: clinical testing	Hereditary Nephrotic Syndromes Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207330.1 First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015	Publications: PubMed (6) PubMed: 9398852‚ 9499425‚ 19484379‚ 20442690‚ 23515051‚ 24161391 Number of individuals with the variant: 1
Likely pathogenic (-)	no assertion criteria provided Method: research	Nephrotic range proteinuria Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001162269.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: male
Pathogenic (Jan 17, 2019)	no assertion criteria provided Method: literature only	Frasier syndrome Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106568.1 First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022	Publications: PubMed (1) PubMed: 30655312
not provided (-)	no classification provided Method: literature only	Wilms tumor 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001478074.2 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 WT1 c.1432+4C>T variant is predicted to interfere with splicing. This variant has been well documented to be pathogenic for Frasier syndrome and steroid-resistant nephrotic syndrome with FSGS (Barbaux et al. 1997. PubMed ID: 9398852; Melo et al. 2002. PubMed ID: 12050205; Li et al. 2010. PubMed ID: 20442690; Lipska et al. 2013. PubMed ID: 23515051). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Comment:

This variant substitutes a C nucleotide with a T nucleotide in the +4 position of the intron 9 splice donor site in the WT1 gene. This variant is also known as c.1447+4C>T and IVS9+4C>T in the literature. RNA studies have found that this variant results in the increased splicing at an alternative donor site in exon 9, resulting in the deletion of the last nine nucleotides of exon 9 and the in-frame deletion of lysine (K), threonine (T) and serine (S) located in between zinc fingers 3 and 4 in the WT1 protein (PMID: 10792605, 34622098). Altered ratio between the two WT1 isoforms with and without the KTS motif are associated with Frasier syndrome (PMID: 9499425, 10561752). This variant has been reported in over 60 individuals affected with Frasier syndromes (PMID: 9398852, 9499425, 10094551, 10505699, 10670748, 10792605, 11007843, 12050205, 22908070, 25623218, 29668062, 34622098, 35211794, 36980135) and related clinical features (PMID: 9529364, 20442690, 23515051, 24161391, 30655312) and three individuals affected with Denys-Drash syndrome (PMID: 9475094). Among individuals diagnosed with Frasier syndrome at least one was affected with Wilms tumor and 19 individuals were affected with gonadal tumors (PMID: 10094551, 22908070, 25623218, 34622098). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

The c.1432+4C>T variant in WT1 has been previously reported in >10 individuals with clinical features of Frasier syndrome, including in at 3 individuals with de novo occurrence (Barbaux 1997, Bastian 20115, Guaragna 2013, Hersmus 2012, Li 2010, Lispka 2013, Wang 2017) and segregated with disease in one affected family member. It was absent from large population studies and has been reported in ClinVar (Variation ID 3500). This variant is variant is located in the 5' splice region. Computational analyses and In vitro functional studies provide some evidence that the c.1432+4C>T variant may impact protein function (Barbaux 1997); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for Frasier syndrome in an autosomal dominant manner based upon de novo occurences, presence in affected individuals, absence from controls and functional evidence. ACMG/AMP Criteria applied: PM6_Strong, PP1_strong, PM2, PS3_supporting (Richards 2015).

Comment:

Published functional studies demonstrate a damaging effect: abnormal gene splicing (Barbaux et al., 1997); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 1658787, 9398852, 22908070, 24856380, 17934764, 27300205, 34392242, 32838737, 31937884, 30348286, 24161391, 19484379, 21508141, 23515051, 20442690, 22815844, 9529364, 25905393, 10792605, 10670748, 9475094, 12050205, 25818337, 26668027, 16439601, 16780544, 10094551, 9499425, 25813279, 28204945, 28921387, 28476686, 29869118, 29668062, 30655312, 32581362, 32887937, 32381729, 32604935)

Comment:

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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with WT1-related disorders (PMID: 9398852, 9499425, 29668062). In at least one individual the variant was observed to be de novo. This variant is also known as IVS9+4C>T. ClinVar contains an entry for this variant (Variation ID: 3500). 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 exon 9 (PMID: 9398852, 12050205). For these reasons, this variant has been classified as Pathogenic.

Comment:

The splice site donor variant c.1447+4C>T in the WT1 gene has been observed in individuals with WT1-related disorders Gomes et al., 2018. Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 Buratti et al., 2007. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This splice variant in intron 9 affects the position of four nucleotides downstream of exon 9. It is submitted to ClinVar as Pathogenic multiple submissions. For these reasons, this variant has been classified as Pathogenic

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease in this gene and is associated with Denys-Drash syndrome (MIM#194080); Frasier syndrome (MIM#136680); Meacham syndrome (MIM#608978) and Nephrotic syndrome, type 4 (MIM#256370) (PMID: 32352694). Loss of function is a known mechanism of disease in this gene and is associated with Wilms tumour, type 1 (MIM#194070). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of total RNA obtained from patients' samples indicated an increase in KTS- transcripts. This is suggestive of an increased use of an alternative splice site, which results in the loss of three amino acids (PMID: 9398852, 12050205). (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. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed as a de novo or inherited variant in multiple individuals with Frasier syndrome (PMID: 9398852, 12050205, 30655312). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Frasier Syndrome: A 15-Year-Old Phenotypically Female Adolescent Presenting with Delayed Puberty and Nephropathy.	Shao Q	Children (Basel, Switzerland)	2023	PMID: 36980135
WT1 complete gonadal dysgenesis with membranoproliferative glomerulonephritis: case series and literature review.	Anderson E	Pediatric nephrology (Berlin, Germany)	2022	PMID: 35211794
Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome.	Tsuji Y	Kidney international reports	2021	PMID: 34622098
WT1 Disorder.	Adam MP	-	2021	PMID: 32352694
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.	Mann N	Journal of the American Society of Nephrology : JASN	2019	PMID: 30655312
Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis.	Gomes NL	Clinical endocrinology	2018	PMID: 29668062
Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome.	Wang F	Pediatric nephrology (Berlin, Germany)	2017	PMID: 28204945
Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis.	Bastian C	Fertility and sterility	2015	PMID: 25813279
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Gonadal tumor in Frasier syndrome: a review and classification.	Ezaki J	Cancer prevention research (Philadelphia, Pa.)	2015	PMID: 25623218
Two distinct WT1 mutations identified in patients and relatives with isolated nephrotic proteinuria.	Guaragna MS	Biochemical and biophysical research communications	2013	PMID: 24161391
Genetic screening in adolescents with steroid-resistant nephrotic syndrome.	Lipska BS	Kidney international	2013	PMID: 23515051
[Clinical and pathological features of Denys-Drash syndrome: report of 3 cases].	Wang HY	Zhonghua er ke za zhi = Chinese journal of pediatrics	2012	PMID: 23302619
Sertoli cell tumor and gonadoblastoma in an untreated 29-year-old 46,XY phenotypic male with Frasier syndrome carrying a WT1 IVS9+4C>T mutation.	Kitsiou-Tzeli S	Hormones (Athens, Greece)	2012	PMID: 22908070
A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation.	Hersmus R	PloS one	2012	PMID: 22815844
WT1 gene mutations in Chinese children with early onset nephrotic syndrome.	Li J	Pediatric research	2010	PMID: 20442690
Single gene disorders.	-	Genomic medicine	2008	PMID: 19484379
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
An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis.	Melo KF	The Journal of clinical endocrinology and metabolism	2002	PMID: 12050205
Absent pubertal development in a child with chronic renal failure: the case of Frasier syndrome.	Bönte A	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2000	PMID: 11007843
WT1 splice-site mutations are rarely associated with primary steroid-resistant focal and segmental glomerulosclerosis.	Denamur E	Kidney international	2000	PMID: 10792605
A Japanese case with Frasier syndrome caused by the splice junction mutation of WT1 gene.	Okuhara K	Endocrine journal	1999	PMID: 10670748
WT1, renal development, and glomerulopathies.	Gubler MC	Advances in nephrology from the Necker Hospital	1999	PMID: 10561752
Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female.	Demmer L	Journal of the American Society of Nephrology : JASN	1999	PMID: 10505699
The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor.	Barbosa AS	Human mutation	1999	PMID: 10094551
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.	Jeanpierre C	American journal of human genetics	1998	PMID: 9529364
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
Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome?	Kikuchi H	Journal of medical genetics	1998	PMID: 9475094
Donor splice-site mutations in WT1 are responsible for Frasier syndrome.	Barbaux S	Nature genetics	1997	PMID: 9398852
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 rs587776577 ...

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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+4C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587776577 ...