ClinVar Miner

Submissions for variant NM_001285829.1(CEBPA):c.-172_-168del (rs1060502121)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464349 SCV000548552 likely pathogenic Acute myeloid leukemia 2016-12-16 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 1 of the CEBPA mRNA (c.186_190delCGACA), causing a frameshift at codon 63. This creates a premature translational stop signal in the only exon of the CEBPA mRNA (p.Asp63Glnfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 296 amino acids of the CEBPA protein. This variant has not been reported in the literature in individuals with a CEBPA-related disease. The region removed by this variant contains two transactivation domains (TAD1 and TAD2) and the basic zipper binding domain (bZip), which are required for CEBPA protein function (PMID: 11242107, 26162409). While experimental studies have not been reported for this specific variant, other experimental studies have shown that N-terminal frameshift variants that occur in the same region as this one can result in the preferential usage of an alternate downstream in-frame methionine at codon 120. Translation starting from this methionine results in a 30 kDa N-terminal truncated isoform of CEBPA that lacks the TAD1 domain, and has been shown to abrogate CEBPA function by acting as a dominant-negative allele (PMID: 11242107). In summary, this variant is a novel frameshift that most likely results in an N-terminal truncated CEBPA protein that disrupts protein function. This evidence suggests that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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