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

gnomAD frequency: 0.00001  dbSNP: rs1423753702

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523951	SCV000617562	pathogenic	not provided	2017-07-18	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000653779	SCV000775669	pathogenic	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2023-05-01	criteria provided, single submitter	clinical testing	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).
Mendelics	RCV000988515	SCV001138263	pathogenic	Drash syndrome	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000709138	SCV001761653	pathogenic	Wilms tumor 1	2021-07-22	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002527574	SCV003606911	pathogenic	Inborn genetic diseases	2022-04-29	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003458448	SCV004183377	pathogenic	WT1-related Wilms tumor	2021-11-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PP1
PreventionGenetics, part of Exact Sciences	RCV003905312	SCV004723748	pathogenic	WT1-related condition	2024-01-28	criteria provided, single submitter	clinical testing	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.