NM_024426.6(WT1):c.1372T>C (p.Cys458Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003062358.3

Allele description [Variation Report for NM_024426.6(WT1):c.1372T>C (p.Cys458Arg)]

NM_024426.6(WT1):c.1372T>C (p.Cys458Arg)

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.1372T>C (p.Cys458Arg)

HGVS:

NC_000011.10:g.32392047A>G
NG_009272.1:g.48495T>C
NM_000378.6:c.1321T>C
NM_001198551.2:c.721T>C
NM_001198552.2:c.670T>C
NM_001367854.1:c.184T>C
NM_001407044.1:c.1366T>C
NM_001407045.1:c.1321T>C
NM_001407047.1:c.1249T>C
NM_001407048.1:c.1231T>C
NM_001407050.1:c.1198T>C
NM_001407051.1:c.610T>C
NM_024424.5:c.1372T>C
NM_024425.2:c.1306T>C
NM_024426.6:c.1372T>CMANE SELECT
NP_000369.4:p.Cys441Arg
NP_001185480.1:p.Cys241Arg
NP_001185480.1:p.Cys241Arg
NP_001185481.1:p.Cys224Arg
NP_001354783.1:p.Cys62Arg
NP_001393973.1:p.Cys456Arg
NP_001393974.1:p.Cys441Arg
NP_001393976.1:p.Cys417Arg
NP_001393977.1:p.Cys411Arg
NP_001393979.1:p.Cys400Arg
NP_001393980.1:p.Cys204Arg
NP_077742.3:p.Cys458Arg
NP_077743.2:p.Cys436Arg
NP_077744.3:p.Cys453Arg
NP_077744.4:p.Cys458Arg
LRG_525t1:c.1357T>C
LRG_525t2:c.721T>C
LRG_525:g.48495T>C
LRG_525p1:p.Cys453Arg
LRG_525p2:p.Cys241Arg
NC_000011.9:g.32413593A>G
NM_001198551.1:c.721T>C
NM_024426.3:c.1357T>C
NR_160306.1:n.1704T>C
NR_176266.1:n.1653T>C

Protein change:

C204R

Molecular consequence:

NM_000378.6:c.1321T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001198551.2:c.721T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001198552.2:c.670T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001367854.1:c.184T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407044.1:c.1366T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407045.1:c.1321T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407047.1:c.1249T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407048.1:c.1231T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407050.1:c.1198T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407051.1:c.610T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024424.5:c.1372T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024425.2:c.1306T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024426.6:c.1372T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_160306.1:n.1704T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Drash syndrome (DDS)
Synonyms:: WILMS TUMOR AND PSEUDO- OR TRUE HERMAPHRODITISM; Wilms tumor and pseudohermaphroditism; Nephropathy, wilms tumor, and genital anomalies; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008682; MedGen: C0950121; Orphanet: 220; OMIM: 194080

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

Name:: Wilms tumor 1 (WT1)
Synonyms:: Wilms tumor, somatic
Identifiers:: MONDO: MONDO:0008679; MedGen: CN033288; Orphanet: 654; OMIM: 194070

Name:: 11p partial monosomy syndrome (WAGR)
Synonyms:: CHROMOSOME 11p13 DELETION SYNDROME; WAGR syndrome; WAGR Complex; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008681; MedGen: C0206115; Orphanet: 893; OMIM: 194072

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003440268	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 29, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9475094, 25818337, 28658201, 27300205, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003440268

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 29, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome?

Kikuchi H, Takata A, Akasaka Y, Fukuzawa R, Yoneyama H, Kurosawa Y, Honda M, Kamiyama Y, Hata J.

J Med Genet. 1998 Jan;35(1):45-8.

PubMed [citation]

PMID:: 9475094
PMCID:: PMC1051186

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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003440268.2

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

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 453 of the WT1 protein (p.Cys453Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with WT1-related conditions (PMID: 9475094, 25818337, 28658201). This variant is also known as p.Cys385Arg. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Cys453 amino acid residue in WT1. Other variant(s) that disrupt this residue have been observed in individuals with WT1-related conditions (PMID: 27300205), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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