ClinVar

Description

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. This variant has not been reported in the literature in individuals with WT1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Gln2*) in the WT1 gene. It is uncertain whether it will result in an absent or disrupted protein product because the in-frame ATG methionine located at codon 69 is preferentially used for translation initiation, and therefore has the potential to rescue WT1 protein function. Based on the reading frame of the WT1 transcript, NM_024426.4, this nonsense variant occurs between a non-canonical translation start site (CTG) at codon 1, which produces a longer isoform with a 68 amino acid extension at the N-terminus (PMID: 8621495), and a known downstream ATG start site at codon 69. The known ATG methionine is primarily used to initiate translation of a biologically active WT1 protein (PMID: 1671709, 18385267, 16987884, 28811308). Experimental studies have shown that knockout mice lacking the N-terminal 68 amino acids develop normally and are reproductive (PMID: 12640141). Based on these results, the impact of this variant on WT1 protein function is uncertain.