ClinVar Miner

Submissions for variant NM_004364.4(CEBPA):c.195_198delinsACG (p.Ser65fs) (rs1600023950)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000798804 SCV000938437 likely pathogenic Acute myeloid leukemia 2019-04-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CEBPA gene (p.Ser65Argfs*95). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 294 amino acids of the CEBPA protein. 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 variant has not been reported in the literature in individuals with CEBPA-related disease. The region disrupted 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). Different variants that affect the CEBPA protein in the same way as the variant observed here (p.A48PfsX112, p.D63EfsX97 and p.P23RfsX137) have been observed families affected with acute myeloid leukemia (PMID: 26162409) This suggests that this variant is also likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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