ClinVar Miner

Submissions for variant NM_001145661.2(GATA2):c.706A>G (p.Met236Val) (rs746737860)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649502 SCV000771331 uncertain significance Lymphedema, primary, with myelodysplasia; Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 236 of the GATA2 protein (p.Met236Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs746737860, ExAC 0.02%). This variant has been observed in individual(s) with clinical features of GATA2-related conditions (PMID: 31309983). ClinVar contains an entry for this variant (Variation ID: 539720). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance 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.
Johns Hopkins Genomics, Johns Hopkins University RCV000853226 SCV000996039 uncertain significance Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency 2019-07-17 criteria provided, single submitter clinical testing This GATA2 variant (rs746737860) is rare (<0.1%) in large population datasets (gnomAD: 6/82258 total alleles; 0.002126%; no homozygotes). This variant is not described in the literature to our knowledge, and a single submitter in ClinVar classifies the sigificance of this variant as uncertain. Two bioinformatic tools queriedpredict that this substitution would be tolerated, however the methionine residue at this position is evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.706A>G is uncertain at this time.

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