WT1:c.1237C>T (p.Arg413Ter) AND Drash syndrome

Clinical significance:Pathogenic (Last evaluated: Jan 28, 2013)

Review status:

classified by single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000003670.1

Allele description [Variation Report for WT1:c.1237C>T (p.Arg413Ter)]

Gene:
WT1:Wilms tumor 1 [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
11p13
Genomic location:
Preferred name:
WT1:c.1237C>T (p.Arg413Ter)
HGVS:
  • NC_000011.10:g.32392717G>A
  • NG_009272.1:g.47825C>T
  • NM_000378.4:c.1237C>T
  • NM_001198551.1:c.652C>T
  • NM_024426.4:c.1288C>T
  • NP_000369.3:p.Arg413Ter
  • NP_001185480.1:p.Arg218Ter
  • NP_077744.3:p.Arg430Ter
  • NC_000011.9:g.32414263G>A
Protein change:
R362*; ARG362TER
Links:
OMIM: 607102.0014; dbSNP: 121907906
NCBI 1000 Genomes Browser:
rs121907906
Molecular consequence:
  • NM_024426.4:c.1288C>T: nonsense [Sequence Ontology: SO:0001587]

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:
MedGen: C0950121; OMIM: 194080; Orphanet: 220
Age of onset:
Neonatal/infancy
Prevalence:
<1 / 1 000 000 220

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Assertion and evidence details

Submission AccessionSubmitterReview StatusClinical Significance
(Last evaluated)
OriginMethodConsequenceCitations
SCV000023833OMIMPathogenic
(Jan 28, 2013)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedAlleles observedFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.

Little MH, Williamson KA, Mannens M, Kelsey A, Gosden C, Hastie ND, van Heyningen V.

Hum Mol Genet. 1993 Mar;2(3):259-64.

PubMed [citation]
PMID:
8388765

Familial Wilms' tumor associated with a WT1 zinc finger mutation.

Kaplinsky C, Ghahremani M, Frishberg Y, Rechavi G, Pelletier J.

Genomics. 1996 Dec 15;38(3):451-3. No abstract available.

PubMed [citation]
PMID:
8975729

Details of each submission

From OMIM, SCV000023833.1

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In a 46,XY patient with Denys-Drash syndrome (194080), Little et al. (1993) identified a C-to-T transition in the WT1 gene, resulting in an arg362-to-ter (R362X) substitution. It was present in heterozygous state in the germline and homozygous state in the tumors. Since the mutation affected zinc finger-2, resulting in a truncated protein interfering with DNA binding, Little et al. (1993) suggested that missense mutations in this region operate by a dominant-negative mechanism.

Kaplinsky et al. (1996) identified a nonsense mutation in the WT1 gene in the Wilms tumor (194070) of 3 sisters who had the same father but 2 different mothers: a C-to-T transition at nucleotide 1084 (relative to the A of the ATG initiation codon) resulted in an arg362-to-ter substitution within zinc finger-2. The mutation was predicted to result in the production of a truncated WT1 polypeptide unable to bind DNA. Two other sibs, both male, were unaffected. Two of the sisters had unilateral Wilms tumor, 1 had bilateral disease. The father, although a carrier, had never developed WT. Kaplinsky et al. (1996) commented that this may be due to incomplete penetrance, which is not gender related. Alternatively, the father could be mosaic for the WT1 mutation, such that mutant cells had not substantially contributed to development of the urogenital system. A third possibility is that genomic imprinting of the mutated WT1 allele is responsible for masking its expression in the male carrier. In the proband, analysis of DNA from a Wilms tumor revealed loss of heterozygosity with retention of 1 set of conformers present in the proband and the father. This pattern is classical for tumor suppressor gene analysis and suggested the unmasking of a recessive mutation by loss of the wildtype allele.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 27, 2014

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