ClinVar Miner

Submissions for variant NM_024426.6(WT1):c.151del (p.Ala51fs) (rs776155094)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722020 SCV000853195 likely pathogenic Pre-B-cell acute lymphoblastic leukemia 2016-03-16 criteria provided, single submitter clinical testing This is a frameshift variant, in which a G is deleted at coding position 136 and is predicted to change an Alanine to a Proline and shift the reading frame.
GeneDx RCV000255852 SCV000322013 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This deletion of one nucleotide in WT1 is denoted c.136delG at the cDNA level and p.Ala46ProfsX31 (A46PfsX31) at the protein level. The normal sequence, with the base that is deleted in brackets, is CGCC[delG]CCGA. The deletion causes a frameshift which changes an Alanine to a Proline at codon 46, and creates a premature stop codon at position 31 of the new reading frame. While this variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, Scharnhorst et al. (1999) has demonstrated the production of a functional truncated WT1 protein through the use of an alternate downstream Methionine at codon 69 (also reported as position 1 using alternate numbering). Additionally, WT1 c.136delG occurs upstream of the start codon of an alternate protein isoform, AWT1, for which translation is initiated at a start site within intron 1 (Dallosso 2004). WT1 c.136delG has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Based on internal observations, multiple carriers of this variant have not presented with Wilms’ tumor or other renal and genitourinary abnormalities, and male carriers have not presented with ambiguous genitalia. Based on currently available evidence, we consider WT1 c.136delG to be a variant of uncertain significance.
Invitae RCV000705265 SCV000834254 uncertain significance Drash syndrome; Frasier syndrome; Wilms tumor 1; Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala46Profs*31) in the WT gene. It is unclear whether it will result in an absent or disrupted protein product because a highly conserved, in-frame methionine located at codon 69 has the potential to rescue protein translation. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with WT1-related disease. ClinVar contains an entry for this variant (Variation ID: 265295). Downstream of the non-canonical translation start site (CTG) at codon 1, the nearest methionine codon that can be used to initiate translation of the WT1 protein lies at codon 69. This downstream in-frame ATG is known as a major initiation site (PMID: 28811308, 16987884, 8621495). The functional significance of the different WT1 protein isoforms is unknown (PMID: 8621495), however mice lacking the N-terminal 68 amino acids develop normally and are fertile (PMID: 12640141). Based on these results, the impact of this variant on WT1 protein function is uncertain. 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.

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