ClinVar Miner

Submissions for variant NM_001145661.2(GATA2):c.30G>T (p.Trp10Cys) (rs367785289)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000551947 SCV000651509 uncertain significance Lymphedema, primary, with myelodysplasia; Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 10 of the GATA2 protein (p.Trp10Cys). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs367785289, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with GATA2-related disease. ClinVar contains an entry for this variant (Variation ID: 472455). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV001007609 SCV001167295 uncertain significance Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency 2019-11-08 criteria provided, single submitter clinical testing This GATA2 variant (rs367785289) is rare (<0.1%) in a large population datasets (gnomAD: 25/255228 total alleles; 0.0098%; no homozygotes). A single submitter in ClinVar classifies the clinical significance of this variant as uncertain5. Three bioinformatic tools queried predict that this substitution would be probably damaging, and the tryptophan residue at this position is evolutionarily conserved across nearly all species assessed. The ClinVar entry for this variant suggests that it may alter exon 2 splicing, however two bioinformatics tools do not support this observation and this variant has not been functionally assessed to our knowledge. Due to lack of functional data, we consider the clinical significance of c.30G>T to be uncertain at this time.

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