chr11-32392019-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_024426.6(WT1):c.1400G>A(p.Arg467Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

WT1
NM_024426.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.87

Publications

34 publications found

Variant links:

Genes affected

WT1 (HGNC:12796): (WT1 transcription factor) This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilms tumor. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation codon upstream of, and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Mar 2015]

WT1 Gene-Disease associations (from GenCC):

Denys-Drash syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
Wilms tumor 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Frasier syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_024426.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-32392020-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 11-32392019-C-T is Pathogenic according to our data. Variant chr11-32392019-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 419332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6 link	c.1400G>A	p.Arg467Gln	missense_variant	Exon 9 of 10	ENST00000452863.10	NP_077744.4	P19544-7Q6PI38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 link	c.1400G>A	p.Arg467Gln	missense_variant	Exon 9 of 10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 26, 2021

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant appears to occur de novo in literature and in an individual tested at Athena Diagnostics with clinical features associated with this gene (PMID: 21499692, 31937884). Additionally, it has been identified in multiple affected individuals (PMID: 16932893, 11322369, 1655284, 1338906, 21125408, 30963316, 9607189, 9475094). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 8810912). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Jun 15, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with Denys Drash syndrome, congenital nephrotic syndrome, or other urogenital abnormalities in the published literature and at GeneDx, including de novo observations with confirmed parentage (Jeanpierre 1998, Schumacher 1998, Kohler 2011, Lehnhardt 2015, Weber 2016, Sen 2017, Brody 2019, Nishi 2019, Sun 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1181G>A (p.Arg394Gln); This variant is associated with the following publications: (PMID: 25818337, 9529364, 9607189, 21508141, 26248470, 28780565, 29474669, 30963316, 32891756, 29568099, 9745866, 29294058, 33726816, 32604935) -

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1

Pathogenic:1

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 462 of the WT1 protein (p.Arg462Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Denys-Drash syndrome and/or clinical features of WT1-related conditions (PMID: 9529364, 9745866, 21508141, 25818337, 26248470, 28780565, 29474669, 30963316, 32604935, 34490048). In at least one individual the variant was observed to be de novo. This variant is also known as p.R394Q and p.R467Q. ClinVar contains an entry for this variant (Variation ID: 419332). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg462 amino acid residue in WT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1327525, 1338906, 1655284, 9529364, 15509792, 17853480, 23715653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Kidney disorder

Pathogenic:1

Aug 22, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

11p partial monosomy syndrome;C0344542:Aniridia 1;C0345967:Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1

Pathogenic:1

Dec 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephrotic syndrome, type 4

Pathogenic:1

Dec 21, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000419332 /PMID: 9529364). Different missense changes at the same codon (p.Arg467Gly, p.Arg467Leu, p.Arg467Pro, p.Arg467Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003487, VCV000003491 /PMID: 1302008, 15150775, 1655284, 20595692 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Drash syndrome

Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated putative nucleic acid binding site (NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg462Trp) variant has commonly been reported in individuals with Denys-Drash syndrome (PMIDs: 30963316, 25349199). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Denys-Drash syndrome or steroid-resistant nephrotic syndrome (PMIDs: 32891756, 30963316, 26248470, 25349199). It has also been reported as pathogenic in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

WT1-related Wilms tumor

Pathogenic:1

Jun 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated -

WT1-related disorder

Pathogenic:1

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The WT1 c.1385G>A variant is predicted to result in the amino acid substitution p.Arg462Gln. In the reported publications, this variant is listed as “p.R394Q”. This variant has previously been reported to be causative for Denys-Drash syndrome (Jeanpierre et al. 1998. PubMed ID: 9529364; Köhler et al. 2011. PubMed ID: 21508141; Lehnhardt et al. 2015. PubMed ID: 25818337). Other missense variants affecting the same amino acid (p.Arg462Gly, p.Arg462Trp, p.Arg462Pro, and p.Arg462Leu) have also been reported in association with nephrotic syndrome, Wilms tumor, and Denys-Drash syndrome (Chernin et al. 2010. PubMed ID: 20595692; Pelletier et al. 1991. PubMed ID: 1655284; Bruening et al. 1992. PubMed ID: 1302008; Royer-Pokora et al. 2004. PubMed ID: 15150775). This variant has not been reported in gnomAD, indicating it is rare. Based on the available evidence, we consider this variant to be pathogenic. -

Wilms tumor 1

Pathogenic:1

Jul 02, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;.;D;.;.;.;.;.

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.71

PhyloP100

7.9

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.5

D;D;D;D;D;.;.;.

REVEL

Uncertain

0.46

Sift

Benign

0.070

T;D;D;D;D;.;.;.

Sift4G

Benign

0.095

T;T;T;T;T;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;.

Vest4

0.85

MVP

0.77

ClinPred

0.90

GERP RS

6.0

gMVP

0.90

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over