ClinVar Miner

Submissions for variant NM_024426.6(WT1):c.1399C>T (p.Arg467Trp) (rs121907900)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467701 SCV000545498 pathogenic Drash syndrome; Frasier syndrome; Wilms tumor 1 2016-04-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 462 of the WT1 protein (p.Arg462Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs121907900, ExAC no frequency). This variant has been reported in multiple individuals affected with Denys-Drash syndrome, Wilms tumor, Meacham syndrome, and diffuse mesangial sclerosis with pseudohermaphroditism and/or Wilms tumor (PMID: 23715653, 1327525, 1338906, 17853480, 9529364). This variant is also known as c.1180C>T (p.R394W) in the literature. ClinVar contains an entry for this variant (Variation ID: 3487). Experimental studies have shown that this missense change alters the ability of WT1 to bind DNA (PMID: 1655284). Furthermore, a mouse model carrying this variant recapitulates the pathology and disease progression seen in individuals with Denys-Drash syndrome (PMID: 15509792). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484426 SCV000566934 pathogenic not provided 2017-11-21 criteria provided, single submitter clinical testing This variant is denoted WT1 c.1384C>T at the cDNA level, p.Arg462Trp (R462W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG) in exon 9. This variant has been commonly published using different nomenclature, WT1 Arg394Trp, and has been observed in numerous individuals presenting with Denys-Drash syndrome (Pelletier 1991, Coppes 1992, Chernin 2010, Lehnhardt 2015, Ahn 2016). In addition, this variant has been published to occur in multiple individuals as a de novo event and functional assays have demonstrated that this variant abolishes DNA binding, both features suggestive of pathogenicity (Pelletier 1991, Little 1995, Duarte 1998, Yu 2012, Alge 2017). WT1 Arg462Trp was not observed in large population cohorts (Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. WT1 Arg462Trp is located in a zinc finger domain and the region important for interaction with target DNA (UniProt). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Athena Diagnostics Inc RCV000484426 SCV000616293 pathogenic not provided 2017-07-06 criteria provided, single submitter clinical testing
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 Diffuse mesangial sclerosis 2007-10-01 no assertion criteria provided literature only

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