Submissions for variant NM_024426.6(WT1):c.1316G>A (p.Arg439His)

dbSNP: rs121907901

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484493	SCV000568577	pathogenic	not provided	2021-12-02	criteria provided, single submitter	clinical testing	Identified in multiple individuals with Denys Drash syndrome as well as in patients with isolated diffuse mesangial sclerosis or early-onset nephrotic syndrome (Schumacher 1998, Pelletier 1991, Royer-Pokora 2004, Nishi 2019); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also reported as c.1097G>A (R366H); This variant is associated with the following publications: (PMID: 16479084, 26882358, 30963316, 15150775, 9607189, 1655284, 29294058, 1338906, 7645607, 9529364, 11322369, 16932893, 17853480, 15026863, 18203154, 26891727, 21434831, 24402088, 8810912, 27719739, 28780565, 30721404, 31937884, 32604935, 29474669)
Johns Hopkins Genomics, Johns Hopkins University	RCV001250546	SCV001425363	pathogenic	Drash syndrome; Frasier syndrome; Nephrotic syndrome, type 4; Wilms tumor 1	2020-05-08	criteria provided, single submitter	clinical testing	This WT1 variant has been reported in multiple individuals presenting with congenital nephrotic syndrome. A functional study has demonstrated that this variant is associated with a decrease in DNA binding affinity when compared to the wild-type protein. WT1 c.1301G>A is located within one of the four zinc finger regions that are important for protein function. This variant is absent from a large population dataset and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across all species assessed. We consider this variant to be pathogenic.
Athena Diagnostics Inc	RCV000484493	SCV001475081	pathogenic	not provided	2020-07-20	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Results on protein functions were inconclusive. 2 de novo cases with parental identity not confirmed. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.
Invitae	RCV001851622	SCV002231581	pathogenic	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2021-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg434 amino acid residue in WT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27300205, 9529364, 7795587, 22172722). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Denys-Drash syndrome and nephrotic syndrome (PMID: 1655284, 26882358, 30721404, 27719739, 30963316). This variant is also known as p.Arg366His in the literature. ClinVar contains an entry for this variant (Variation ID: 3488). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 434 of the WT1 protein (p.Arg434His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243617	SCV002512636	pathogenic	Nephrotic syndrome, type 4	2021-10-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong
Fulgent Genetics, Fulgent Genetics	RCV002496247	SCV002810914	pathogenic	Aniridia 1; Drash syndrome; Frasier syndrome; Meacham syndrome; Mesothelioma, malignant; Nephrotic syndrome, type 4; Wilms tumor 1; 11p partial monosomy syndrome	2022-01-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147274	SCV003835055	pathogenic	Wilms tumor 1	2021-06-11	criteria provided, single submitter	clinical testing
OMIM	RCV000003659	SCV000023822	pathogenic	Drash syndrome	2008-02-15	no assertion criteria provided	literature only
Human Genetics Disease in Children – Taif University, Taif University	RCV000003659	SCV000265969	pathogenic	Drash syndrome	2016-01-01	no assertion criteria provided	clinical testing