rs121907900

Variant names:

• chr11-32392020-G-A
• rs121907900
• NM_024426.6:c.1399C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32392020-G-A
• chr11-32392020-G-C
• chr11-32392020-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_024426.6(WT1):​c.1399C>T​(p.Arg467Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 5.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-32392019-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• PP5: Variant 11-32392020-G-A is Pathogenic according to our data. Variant chr11-32392020-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32392020-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.1399C>T	p.Arg467Trp	missense_variant	Exon 9 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1399C>T	p.Arg467Trp	missense_variant	Exon 9 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Dec 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: variant abolishes DNA binding (Little 1995, Duarte 1998, Barrera 2016); 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 Arg394Trp; This variant is associated with the following publications: (PMID: 25818337, 10470095, 25501161, 28921387, 28204945, 9460996, 26069768, 20595692, 31937884, 24402088, 15509792, 11299720, 23715653, 27013732, 27899157, 28068926, 28476686, 28720077, 29869118, 28851938, 29982877, 29320783, 29801916, 30963316, 31278746, 31707902, 1655284, 27300205, 1327525, 7795587, 8486616, 32581362, 34031707, 33742552, 32604935, 32352694, 29294058, 34386660) -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 05, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features of WT1-related disorders, and appears to occur de novo in several cases. In some published literature, this variant is referred to as c.1399C>T (p.Arg467Trp), c.748C>T (p.Arg250Trp), or c.1384C>T (p.Arg462Trp). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12970737, 15509792, 17496156, 23497137, 30450160, 31583044) At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Drash syndrome Pathogenic:3

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 25, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wilms tumor 1 Pathogenic:2 Other:1

Feb 01, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The WT1 c.1348C>T (p.Arg450Trp) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. Functional studies show that the variant alters the WT1 protein function (PMID: 1655284; 15509792). This variant has been reported in individuals with WT1-related conditions (PMID: 1655284, 1327525, 1338906, 9529364, 23715653). It has therefore been classified as pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

The most common pathogenic variant -

Nephrotic syndrome, type 4 Pathogenic:2

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 01, 2023

Precision Medicine Center, Zhengzhou University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2,PM2_p,PP3,PP4 -

Steroid-resistant nephrotic syndrome;C0445118:Nephrotic range proteinuria Pathogenic:1

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NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Feb 03, 2025

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 tryptophan, which is neutral and slightly polar, at codon 462 of the WT1 protein (p.Arg462Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Denys-Drash syndrome, Wilms tumor, Meacham syndrome, and diffuse mesangial sclerosis with pseudohermaphroditism and/or Wilms tumor (PMID: 1327525, 1338906, 9529364, 17853480, 23715653). In at least one individual the variant was observed to be de novo. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this WT1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 485,843 individuals referred to our laboratory for WT1 testing. This variant is also known as c.1180C>T (p.R394W). ClinVar contains an entry for this variant (Variation ID: 3487). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt WT1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects WT1 function (PMID: 1655284, 15509792). For these reasons, this variant has been classified as Pathogenic. -

Kidney disorder Pathogenic:1

Feb 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Pathogenic:1

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meacham syndrome Pathogenic:1

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

WT1-related disorder Pathogenic:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The WT1 c.1384C>T variant is predicted to result in the amino acid substitution p.Arg462Trp. This variant has been reported in numerous patients to be causative for Denys-Drash syndrome/Wilms tumor and has been previously documented as c.1180C>T (p.Arg394Trp) (Pelletier et al. 1991. PubMed ID: 1655284; Schumacher et al. 1998. PubMed ID: 9607189; Zhu et al. 2013. PubMed ID: 23715653; Lehnhardt et al. 2015. PubMed ID: 25818337; Barrera et al. 2016. PubMed ID: 27013732; Eggers et al. 2016. PubMed ID: 27899157, referred as p.R445W in Suppl. Table 1). In at least two individuals, this variant was observed to be de novo (Gambale et al. 2019. PubMed ID: 31278746; Nagano et al. 2020. PubMed ID: 31937884). Different substitutions at the same position (p.Arg462Gly, p.Arg467Gln, p.Arg467Pro and p.Arg467Leu) have also been reported to be causative for Denys-Drash syndrome/Wilms tumor/nephrotic syndrome (see for example, Bruening et al. 1992. PubMed ID: 1302008; Jeanpierre et al. 1998. PubMed ID: 9529364; Royer-Pokora et al. 2004. PubMed ID: 15150775; Chernin et al. 2010. PubMed ID: 20595692). The c.1384C>T (p.Arg462Trp) variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D;.;D;.;.;.;.;.
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.081	T
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;.;.;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.87
MVP		0.75
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs121907900; hg19: chr11-32413566; COSMIC: COSV60066486; COSMIC: COSV60066486;