ClinVar Miner

Submissions for variant NM_024426.6(WT1):c.1388G>A (p.Arg463Gln)

dbSNP: rs1037084691
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV001195711 SCV001366115 uncertain significance Focal segmental glomerulosclerosis 2019-05-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001302945 SCV001492173 uncertain significance Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome 2022-07-21 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects WT1 function (PMID: 25145932). 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. ClinVar contains an entry for this variant (Variation ID: 599100). This variant is also known as p.Arg463Gln. This missense change has been observed in individual(s) with disorder of sex development (DSD) and focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome (SRNS) (PMID: 25145932, 25383892, 30406062, 33226606, 34386660). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 458 of the WT1 protein (p.Arg458Gln).
Fulgent Genetics, Fulgent Genetics RCV001535956 SCV001752617 pathogenic Aniridia 1; Drash syndrome; Frasier syndrome; Meacham syndrome; Mesothelioma, malignant; Nephrotic syndrome, type 4; Wilms tumor 1; 11p partial monosomy syndrome 2021-06-30 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000735697 SCV002581114 likely pathogenic Nephrotic syndrome, type 4 2022-07-25 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV003338777 SCV004047858 pathogenic Drash syndrome criteria provided, single submitter clinical testing The missense variant c.1388G>A (p.Arg463Gln) in WT1 has alternately been reported as p.Arg458Gln in unrelated patients with disorder of sex development, focal segmental glomerulosclerosis and steroid resistant nephrotic syndrome (Baxter et al. 2015, Hall et al. 2015, Varner et al. 2018, Sadowski et al. 2015). Functional studies revealed a damaging effect. (Hall et al. 2015). The p.Arg463Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The p.Arg463Gln variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Uncertain Significance. The amino acid Arg at position 463 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The p.Arg463Gln variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg463Gln in WT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV004702388 SCV005202004 likely pathogenic not provided 2023-09-22 criteria provided, single submitter clinical testing Published functional studies demonstrate the R48Q variant leads to decreased luciferase activity compared to wildtype, hinders DNA binding ability and causes an increase in apoptosis (PMID: 25145932, 34386660); 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; This variant is associated with the following publications: (PMID: 25145932, 35561789, 33226606, 29556761, 30406062, 25349199, 34386660, 25383892, 34727091)
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000735697 SCV000863845 pathogenic Nephrotic syndrome, type 4 2018-03-27 no assertion criteria provided clinical testing

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