Submissions for variant NM_024426.6(WT1):c.1399C>T (p.Arg467Trp)

dbSNP: rs121907900

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467701	SCV000545498	pathogenic	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2023-03-14	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WT1 function (PMID: 1655284, 15509792). ClinVar contains an entry for this variant (Variation ID: 3487). This variant is also known as c.1180C>T (p.R394W). 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. This variant is not present in population databases (gnomAD no frequency). 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).
GeneDx	RCV000484426	SCV000566934	pathogenic	not provided	2022-12-22	criteria provided, single submitter	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)
Athena Diagnostics	RCV000484426	SCV000616293	pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000003656	SCV001138261	pathogenic	Drash syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003656	SCV001521533	pathogenic	Drash syndrome	2019-07-25	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293973	SCV002587462	pathogenic	Kidney disorder	2018-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482821	SCV002793374	pathogenic	Aniridia 1; Drash syndrome; Frasier syndrome; Meacham syndrome; Mesothelioma, malignant; Nephrotic syndrome, type 4; Wilms tumor 1; 11p partial monosomy syndrome	2021-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001290016	SCV004040758	pathogenic	Wilms tumor 1	2023-02-01	criteria provided, single submitter	clinical testing
Precision Medicine Center, Zhengzhou University	RCV000003658	SCV004218500	likely pathogenic	Nephrotic syndrome, type 4	2023-12-01	criteria provided, single submitter	clinical testing	PS2,PM2_p,PP3,PP4
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001290016	SCV005402370	pathogenic	Wilms tumor 1	2024-04-17	criteria provided, single submitter	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.
OMIM	RCV000003656	SCV000023819	pathogenic	Drash syndrome	2007-10-01	no assertion criteria provided	literature only
OMIM	RCV000003657	SCV000023820	pathogenic	Meacham syndrome	2007-10-01	no assertion criteria provided	literature only
OMIM	RCV000003658	SCV000023821	pathogenic	Nephrotic syndrome, type 4	2007-10-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003819	SCV001162270	likely pathogenic	Steroid-resistant nephrotic syndrome; Nephrotic range proteinuria		no assertion criteria provided	research
GeneReviews	RCV001290016	SCV001478073	not provided	Wilms tumor 1		no assertion provided	literature only	The most common pathogenic variant
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000484426	SCV001927605	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484426	SCV001956490	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739285	SCV005359052	pathogenic	WT1-related disorder	2024-08-05	no assertion criteria provided	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.