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

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000030876.11

Allele description [Variation Report for NM_024426.6(WT1):c.1447+5G>A]

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

Gene:

WT1:WT1 transcription factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p13

Genomic location:

Preferred name:

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

Other names:

splice site; 1432+5G>A; IVS9+5G>A

HGVS:

NC_000011.10:g.32391967C>T
NG_009272.1:g.48575G>A
NM_000378.6:c.1387+14G>A
NM_001198551.2:c.787+14G>A
NM_001198552.2:c.745+5G>A
NM_001367854.1:c.259+5G>A
NM_001407044.1:c.1432+14G>A
NM_001407045.1:c.1396+5G>A
NM_001407046.1:c.1354+699G>A
NM_001407047.1:c.1315+14G>A
NM_001407048.1:c.1306+5G>A
NM_001407049.1:c.1303+699G>A
NM_001407050.1:c.1273+5G>A
NM_001407051.1:c.685+5G>A
NM_024424.5:c.1438+14G>A
NM_024426.6:c.1447+5G>AMANE SELECT
LRG_525:g.48575G>A
NC_000011.9:g.32413513C>T
NM_024426.2:c.1228+5G>A
NM_024426.4:c.1432+5G>A

Nucleotide change:

IVS9DS, G-A, +5

Links:

OMIM: 607102.0009; OMIM: 607102.0020; dbSNP: rs587776576

NCBI 1000 Genomes Browser:

rs587776576

Molecular consequence:

NM_000378.6:c.1387+14G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001198551.2:c.787+14G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001198552.2:c.745+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001367854.1:c.259+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407044.1:c.1432+14G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407045.1:c.1396+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407046.1:c.1354+699G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407047.1:c.1315+14G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407048.1:c.1306+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407049.1:c.1303+699G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407050.1:c.1273+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407051.1:c.685+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_024424.5:c.1438+14G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_024426.6:c.1447+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Frasier syndrome
Identifiers:: MONDO: MONDO:0007635; MeSH: D052159; MedGen: C0950122; Orphanet: 347; OMIM: 136680

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023839	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 1998)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9499425, 1658787
SCV000731767	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jan 10, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9499425, 25818337, 23515051, 24856380, 1302008, 23295293, 28204945, 24033266
SCV001523310	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 16, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086640	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1302008, 9499425, 16439601, 25623218, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Alternative splicing and genomic structure of the Wilms tumor gene WT1.

Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE.

Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9618-22.

PubMed [citation]

PMID:: 1658787
PMCID:: PMC52769

Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1.

Lehnhardt A, Karnatz C, Ahlenstiel-Grunow T, Benz K, Benz MR, Budde K, Büscher AK, Fehr T, Feldkötter M, Graf N, Höcker B, Jungraithmayr T, Klaus G, Koehler B, Konrad M, Kranz B, Montoya CR, Müller D, Neuhaus TJ, Oh J, Pape L, Pohl M, et al.

Clin J Am Soc Nephrol. 2015 May 7;10(5):825-31. doi: 10.2215/CJN.10141014. Epub 2015 Mar 27.

PubMed [citation]

PMID:: 25818337
PMCID:: PMC4422247

See all PubMed Citations (12)

Details of each submission

From OMIM, SCV000023839.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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).)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731767.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

From Baylor Genetics, SCV001523310.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086640.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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