Submissions for variant NM_032638.5(GATA2):c.1081C>T (p.Arg361Cys)

gnomAD frequency: 0.00001  dbSNP: rs1426175410

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000528994	SCV000651484	pathogenic	Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections	2022-09-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg361 amino acid residue in GATA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21892158). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 472431). This missense change has been observed in individual(s) with clinical features of GATA2-related conditions (PMID: 23502222, 24077845, 24266605, 25879889, 26812071, 27418648, 32135276). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 361 of the GATA2 protein (p.Arg361Cys).
PreventionGenetics, part of Exact Sciences	RCV000984821	SCV001132703	likely pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing
Molecular Pathology Research Laboratory, SA Pathology	RCV001542237	SCV001760905	likely pathogenic	Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML	2021-07-06	criteria provided, single submitter	curation	PS4, PM1, PM5, PP3
GeneDx	RCV000984821	SCV001781806	pathogenic	not provided	2020-09-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32135276, 25879889, 24227816, 23502222, 31309983, 30933029, 31413257, 26702063, 30521493, 27418648, 24077845, 24266605, 21892158, 26812071)
Genetic Services Laboratory, University of Chicago	RCV000984821	SCV002069045	likely pathogenic	not provided	2018-04-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224332	SCV003920000	pathogenic	Acute myeloid leukemia; Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections; Myelodysplastic syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in at least 7 individuals with a range of clinical features including myelodysplastic syndrome, various types of cytopenia, recurrent infection, and lymphedema (Hsu 2013 PMID: 23502222; Webb 2016 PMID: 26812071; Gardner 2019 PMID: 30933029; Shamriz 2022 PMID: 35603181), including at least once as a de novo variant (Simon 2020 PMID: 32135276); additionally, this variant was found to segregate in at least 3 family members who were apparently asymptomatic but showed similarly reduced cell counts as their symptomatic family members (Svobodova 2013 PMID: 25879889; Nováková 2016 PMID: 27013649). This variant is present in 1 total allele in the Genome Aggregation Database (Highest reported MAF: 0.02% [1/5180]; https://gnomad.broadinstitute.org/variant/3-128481881-G-A?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, incomplete penetrance, and/or variable expressivity. This variant is also present in ClinVar, with classifications ranging from likely pathogenic to pathogenic (Variation ID: 472431). Evolutionary conservation and computational predictive tools strongly suggest that this variant may impact the protein. In summary, this variant is classified as pathogenic.