VCV000449416.19 - ClinVar

NM_024426.6(WT1):c.1120C>T (p.Arg374Ter)

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.

(7)

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

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.1120C>T (p.Arg374Ter)

Variation ID: 449416 Accession: VCV000449416.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p13 11: 32396401 (GRCh38) [ NCBI UCSC ] 11: 32417947 (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	Dec 19, 2017	Oct 8, 2024	May 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024426.6:c.1120C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077744.4:p.Arg374Ter	nonsense
NM_000378.6:c.1069C>T	NP_000369.4:p.Arg357Ter	nonsense
NM_001198551.2:c.469C>T	NP_001185480.1:p.Arg157Ter	nonsense
NM_001198552.2:c.418C>T	NP_001185481.1:p.Arg140Ter	nonsense
NM_001367854.1:c.-69C>T		5 prime UTR
NM_001407044.1:c.1114C>T	NP_001393973.1:p.Arg372Ter	nonsense
NM_001407045.1:c.1069C>T	NP_001393974.1:p.Arg357Ter	nonsense
NM_001407046.1:c.1120C>T	NP_001393975.1:p.Arg374Ter	nonsense
NM_001407047.1:c.997C>T	NP_001393976.1:p.Arg333Ter	nonsense
NM_001407048.1:c.1069C>T	NP_001393977.1:p.Arg357Ter	nonsense
NM_001407049.1:c.1069C>T	NP_001393978.1:p.Arg357Ter	nonsense
NM_001407050.1:c.946C>T	NP_001393979.1:p.Arg316Ter	nonsense
NM_001407051.1:c.358C>T	NP_001393980.1:p.Arg120Ter	nonsense
NM_024424.5:c.1120C>T	NP_077742.3:p.Arg374Ter	nonsense
NM_024425.2:c.1054C>T	NP_077743.2:p.Arg352Ter	nonsense
NR_160306.1:n.1452C>T		non-coding transcript variant
NR_176266.1:n.1401C>T
NC_000011.10:g.32396401G>A
NC_000011.9:g.32417947G>A
NG_009272.1:g.44141C>T
LRG_525:g.44141C>T
LRG_525t1:c.1105C>T	LRG_525p1:p.Arg369Ter
LRG_525t2:c.469C>T	LRG_525p2:p.Arg157Ter

... more HGVS ... less HGVS

Protein change

R157*, R374*, R357*, R140*, R316*, R333*, R372*, R120*, R352*

Other names

Canonical SPDI

NC_000011.10:32396400: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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA379960070 dbSNP: rs1423753702 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	914	1671

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 18, 2017	RCV000523951.2
Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Jul 22, 2021	RCV000709138.6
11p partial monosomy syndrome Drash syndrome Frasier syndrome Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	May 1, 2023	RCV000653779.10
Drash syndrome	Pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000988515.2
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 29, 2022	RCV002527574.1
WT1-related Wilms tumor	Pathogenic (1)	criteria provided, single submitter	Nov 27, 2021	RCV003458448.1
WT1-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 28, 2024	RCV004553140.2

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 (Jul 18, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617562.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: The R369X variant in the WT1 gene has been reported in at least two individuals with Wilms tumor, one of whom had bilateral disease (Schumacher … (more) The R369X variant in the WT1 gene has been reported in at least two individuals with Wilms tumor, one of whom had bilateral disease (Schumacher 1997). The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We interpret R369X as a pathogenic variant. (less)
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Drash syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138263.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Wilms tumor 1 Affected status: yes Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV001761653.1 First in ClinVar: Jul 29, 2021 Last updated: Jul 29, 2021	Comment: The WT1 c.1054C>T (p.Arg352Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This … (more) The WT1 c.1054C>T (p.Arg352Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant corresponds to the c.1120C>T (p.Arg374Ter) in the transcript NM_024426.6. This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). It has been reported in the literature in two siblings affected with Wilms tumor, one of whom had bilateral disease, as well as two additional individuals with loss of the wild-type allele in the tumor (PS4; PMID: 9108089, internal data). In summary, this variant meets criteria to be classified as of pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting. (less)
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003606911.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 19048299 Comment: The c.1105C>T (p.R369) alteration, located in exon 7 (coding exon 7) of the WT1 gene, consists of a C to T substitution at nucleotide position … (more) The c.1105C>T (p.R369) alteration, located in exon 7 (coding exon 7) of the WT1 gene, consists of a C to T substitution at nucleotide position 1105. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 369. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (1/31402) total alleles studied. This alteration has been reported de novo in a male patient with bilateral cryptorchidism, nystagmus, mild proteinuria, and Wilms tumor (Terenziani, 2009). Based on the available evidence, this alteration is classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Nov 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	WT1-related Wilms tumor Affected status: unknown Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV004183377.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: ACMG classification criteria: PVS1, PS4, PM2, PP1 Geographic origin: Brazil
Pathogenic (May 01, 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: SCV000775669.6 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 9108089‚ 15150775 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449416). This variant is also known … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449416). This variant is also known as p.Arg301. This premature translational stop signal has been observed in individual(s) with Wilms tumors (PMID: 9108089). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg369) in the WT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WT1 are known to be pathogenic (PMID: 15150775). (less)
Pathogenic (Jan 28, 2024)	no assertion criteria provided Method: clinical testing	WT1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004723748.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The WT1 c.1105C>T variant is predicted to result in premature protein termination (p.Arg369). This variant has been reported in individuals with WT1-related disorders (see for … (more) The WT1 c.1105C>T variant is predicted to result in premature protein termination (p.Arg369). This variant has been reported in individuals with WT1-related disorders (see for example, reported as codon 301 Arg to Stop at Table 2 of Schumacher et al. 1997. PubMed ID: 9108089; p.Arg369Ter in Akramov et al. 2021. PubMed ID: 34106634; p.Q369X in Terenziani et al. 2009. PubMed ID: 19048299). To our knowledge, this variant has not been reported in continental populations in a large population database, indicating this variant is rare. Nonsense variants in WT1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

The R369X variant in the WT1 gene has been reported in at least two individuals with Wilms tumor, one of whom had bilateral disease (Schumacher 1997). The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We interpret R369X as a pathogenic variant.

Comment:

The WT1 c.1054C>T (p.Arg352Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant corresponds to the c.1120C>T (p.Arg374Ter) in the transcript NM_024426.6. This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). It has been reported in the literature in two siblings affected with Wilms tumor, one of whom had bilateral disease, as well as two additional individuals with loss of the wild-type allele in the tumor (PS4; PMID: 9108089, internal data). In summary, this variant meets criteria to be classified as of pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting.

Comment:

The c.1105C>T (p.R369*) alteration, located in exon 7 (coding exon 7) of the WT1 gene, consists of a C to T substitution at nucleotide position 1105. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 369. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (1/31402) total alleles studied. This alteration has been reported de novo in a male patient with bilateral cryptorchidism, nystagmus, mild proteinuria, and Wilms tumor (Terenziani, 2009). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449416). This variant is also known as p.Arg301*. This premature translational stop signal has been observed in individual(s) with Wilms tumors (PMID: 9108089). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg369*) in the WT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WT1 are known to be pathogenic (PMID: 15150775).

Comment:

The WT1 c.1105C>T variant is predicted to result in premature protein termination (p.Arg369*). This variant has been reported in individuals with WT1-related disorders (see for example, reported as codon 301 Arg to Stop at Table 2 of Schumacher et al. 1997. PubMed ID: 9108089; p.Arg369Ter in Akramov et al. 2021. PubMed ID: 34106634; p.Q369X in Terenziani et al. 2009. PubMed ID: 19048299). To our knowledge, this variant has not been reported in continental populations in a large population database, indicating this variant is rare. Nonsense variants in WT1 are expected to be pathogenic. This variant is interpreted as pathogenic.

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
A novel WT1 mutation in a 46,XY boy with congenital bilateral cryptorchidism, nystagmus and Wilms tumor.	Terenziani M	Pediatric nephrology (Berlin, Germany)	2009	PMID: 19048299
Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development.	Royer-Pokora B	American journal of medical genetics. Part A	2004	PMID: 15150775
Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology.	Schumacher V	Proceedings of the National Academy of Sciences of the United States of America	1997	PMID: 9108089

Text-mined citations for rs1423753702 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_024426.6(WT1):c.1120C>T (p.Arg374Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1423753702 ...