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

dbSNP: rs1037084691

Total submissions: 6

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
Invitae	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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000735697	SCV000863845	pathogenic	Nephrotic syndrome, type 4	2018-03-27	no assertion criteria provided	clinical testing