ClinVar Miner

Submissions for variant NM_001145661.2(GATA2):c.1075T>G (p.Leu359Val) (rs1060500091)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457272 SCV000541512 uncertain significance Lymphedema, primary, with myelodysplasia; Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency 2016-10-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 359 of the GATA2 protein (p.Leu359Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with thrombocytopenia and acute myeloid leukemia who had a family history of thrombocytopenia and myelodysplastic syndrome in multiple relatives (PMID: 24754962). However, a second GATA2 variant in the adjacent codon (p.Thr358Lys) was identified on the same allele in this same individual and it should be noted that the germline nature of these variants were not definitively established. This variant has also been reported as a recurrent somatic variant in individuals undergoing chronic myeloid leukemia progression from chronic phase to blast crisis (PMID: 18250304). This variant is located in the ZF2 domain, which is responsible for DNA binding, self-association, and heterodimerization with the GATA2 co-factor PU.1 (PMID: 25707267). Experimental studies have shown that, compared to wildtype protein, this missense change increases GATA2 transactivation activity, enhances binding to DNA, and enhances binding to PU.1, resulting in inhibition of PU.1-mediated transactivation on several target promoters (PMID: 18250304, 25676417). In summary, this variant is a rare missense change that has been shown to affect protein function in vitro. While it is absent from the population and reported in an affected individual, the germline nature of the variant in that individual is not established. In the absence of additional genetic data, this variant has been classified as a Variant of Uncertain Significance.

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