ClinVar Miner

Submissions for variant NM_004364.5(CEBPA):c.60dup (p.Ser21fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001379181 SCV001576932 likely pathogenic Acute myeloid leukemia 2020-02-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CEBPA gene (p.Ser21Glufs*87). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 338 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 conditions. The region disrupted by this variant contains one transactivation domain (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). While functional studies have not been performed to directly test the effect of this variant on CEBPA protein function, this suggests that disruption of this region of the protein is 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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