Submissions for variant NM_032638.5(GATA2):c.1192C>T (p.Arg398Trp)

dbSNP: rs387906629

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502442	SCV000594916	pathogenic	Leukemia, acute myeloid, susceptibility to	2016-06-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000984831	SCV001132714	pathogenic	not provided	2016-10-09	criteria provided, single submitter	clinical testing
Invitae	RCV001384284	SCV001583727	pathogenic	Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections	2023-07-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 29709). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 398 of the GATA2 protein (p.Arg398Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GATA2 deficiency (PMID: 21670465, 21765025). 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) performed at Invitae indicates that this missense variant is expected to disrupt GATA2 protein function. Experimental studies have shown that this missense change affects GATA2 function (PMID: 29882021). For these reasons, this variant has been classified as Pathogenic.
Molecular Pathology Research Laboratory, SA Pathology	RCV001541956	SCV001760591	pathogenic	Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML	2021-07-06	criteria provided, single submitter	curation	PS3, PS4, PM1, PM2, PM5, PP1_Moderate, PP3
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000022559	SCV002577573	pathogenic	Monocytopenia with susceptibility to infections	2022-02-17	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP2, PP3, PP5
Mayo Clinic Laboratories, Mayo Clinic	RCV000984831	SCV004226759	pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	PP3, PM1, PM2_supporting, PS3, PS4
Ambry Genetics	RCV004018663	SCV005029320	pathogenic	Inborn genetic diseases	2023-12-15	criteria provided, single submitter	clinical testing	The p.R398W pathogenic mutation (also known as c.1192C>T), located in coding exon 5 of the GATA2 gene, results from a C to T substitution at nucleotide position 1192. The arginine at codon 398 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in multiple unrelated individuals with GATA2 deficiency syndrome (Dickinson RE et al. Blood, 2011 Sep;118:2656-8; Hsu AP et al. Blood, 2011 Sep;118:2653-5; Churpek JE et al. Blood, 2015 Nov;126:2484-90; Mardahl M et al. Br J Haematol, 2019 Aug;186:471-476; West RR et al. Blood Adv, 2022 Feb;6:793-807). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000022559	SCV000043848	pathogenic	Monocytopenia with susceptibility to infections	2011-09-08	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445214	SCV000504646	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only