Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003778906 | SCV004576376 | uncertain significance | Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections | 2023-10-26 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 268 of the GATA2 protein (p.Gly268Arg). This variant is present in population databases (rs764747992, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2443136). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATA2 protein function. 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. |
| Ambry Genetics | RCV004978800 | SCV005596793 | uncertain significance | Inborn genetic diseases | 2024-10-29 | criteria provided, single submitter | clinical testing | The p.G268R variant (also known as c.802G>A), located in coding exon 2 of the GATA2 gene, results from a G to A substitution at nucleotide position 802. The glycine at codon 268 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Genetic Services Laboratory, |
RCV003151528 | SCV003839553 | uncertain significance | not specified | 2022-07-27 | no assertion criteria provided | clinical testing | DNA sequence analysis of the GATA2 gene demonstrated a sequence change, c.802G>A, in exon 3 that results in an amino acid change, p.Gly268Arg. This sequence change does not appear to have been previously described in individuals with GATA2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.013% in the African subpopulation (dbSNP rs764747992. The p.Gly268Arg change affects a highly conserved amino acid residue located in a domain of the GATA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly268Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly268Arg change remains unknown at this time. Germline pathogenic variants in GATA2 have been described in association with immunodeficiency [OMIM# 614172] and Emberger syndrome [OMIM# 614038]. Clinical phenotypes include immunodeficiency with marked susceptibility to EBV, HPV, and other viruses, atypical mycobacteria, and fungal infections. Transformation to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is usually preceded by a period of bone marrow failure. Monosomy 7 and/or somatic ASXL1 mutations are often present at transformation (PMID: 30047422). |