Submissions for variant NM_032638.5(GATA2):c.445G>A (p.Gly149Arg)

gnomAD frequency: 0.00009  dbSNP: rs753645971

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458357	SCV000541509	likely benign	Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections	2024-12-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765712	SCV000897073	uncertain significance	Acute myeloid leukemia; Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections; Myelodysplastic syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821227	SCV002067097	uncertain significance	not specified	2020-09-28	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GATA2 gene demonstrated a sequence change, c.445G>A, in exon 3 that results in an amino acid change, p.Gly149Arg. This sequence change does not appear to have been previously described in patients with GATA2-related disorders and has been described in the gnomAD database with a frequency of 0.053% in the Latino sub-population (dbSNP rs753645971). The p.Gly149Arg change affects a poorly 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.Gly149Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly149Arg change remains unknown at this time.
GeneDx	RCV003236800	SCV003935778	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with gastric cancer and in a patient with leukemia (AML); however, it is unclear whether the variant was germline or somatic in the latter individual (Aguirre-Ruiz et al., 2020; Herrera-Pariente et al., 2021); This variant is associated with the following publications: (PMID: 30755392, 33255857, 33525650)
Baylor Genetics	RCV004567941	SCV005058898	uncertain significance	Acute myeloid leukemia	2024-02-12	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004787706	SCV005402146	uncertain significance	GATA2 deficiency with susceptibility to MDS/AML	2024-02-15	criteria provided, single submitter	clinical testing	The GATA2 c.445G>A (p.Gly149Arg) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, but functional studies have not been performed. This variant has not been reported in individuals presenting with GATA2-associated clinical phenotypes. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003972754	SCV004790409	likely benign	GATA2-related disorder	2022-05-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).