Submissions for variant NM_024426.6(WT1):c.1104A>T (p.Arg368Ser)

gnomAD frequency: 0.00001  dbSNP: rs544966826

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000791867	SCV000931134	uncertain significance	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 363 of the WT1 protein (p.Arg363Ser). This variant is present in population databases (rs544966826, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of WT1-related conditions (PMID: 25451826, 36349777). ClinVar contains an entry for this variant (Variation ID: 639136). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV003396375	SCV004105669	uncertain significance	WT1-related condition	2023-01-24	criteria provided, single submitter	clinical testing	The WT1 c.1089A>T variant is predicted to result in the amino acid substitution p.Arg363Ser. This variant has been reported in an individual with azoospermia (Seabra CM et al 2014. PubMed ID: 25451826). This variant is reported in 0.055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-32421503-T-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358073	SCV001553721	uncertain significance	not provided		no assertion criteria provided	clinical testing	The WT1 p.Arg151Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs544966826) and in control databases in 11 of 282804 chromosomes at a frequency of 0.000039 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 11 of 19952 chromosomes (freq: 0.000551), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Other or South Asian populations. The p.Arg151 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and only two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.