Submissions for variant NM_024426.6(WT1):c.680T>C (p.Phe227Ser)

dbSNP: rs1554945235

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000653780	SCV000775670	uncertain significance	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 222 of the WT1 protein (p.Phe222Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with WT1-associated disease (PMID: 24402088). This variant is also known as F154S. ClinVar contains an entry for this variant (Variation ID: 543117). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt WT1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects WT1 function (PMID: 22465478). 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.
All of Us Research Program, National Institutes of Health	RCV004004097	SCV004834031	uncertain significance	Wilms tumor 1	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 222 of the WT1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts WT1 function in growth suppression assays on ex vivo cell lines (PMID: 10224085) and also its function in transcription activation and suppression in some but not all gene promoters tested (PMID: 10224085, 12855602, 12882970, 22465478, 24402088). To our knowledge, this variant has not been reported as a germline mutation in individuals affected with Wilms tumor in the literature. This variant has been detected in an individual affected with steroid-resistant nephrotic syndrome (PMID: 24402088). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.