ClinVar Miner

Submissions for variant NM_001145661.2(GATA2):c.1081C>T (p.Arg361Cys) (rs1426175410)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000528994 SCV000651484 likely pathogenic Lymphedema, primary, with myelodysplasia; Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency 2018-03-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 361 of the GATA2 protein (p.Arg361Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with leukocytopenia in a single family (PMID: 25879889), and has been reported in several individuals affected with myelodysplastic syndrome, monocytopenia, and monocytopenia with Mycobacterium avium complex (MonoMAC syndrome) (PMID: 23502222, 26812071, 24266605, 27418648, 24077845). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg361Leu) has been determined to be pathogenic (PMID: 21892158). This suggests that the arginine residue is critical for GATA2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics,PreventionGenetics 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 Lymphedema, primary, with myelodysplasia; 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)

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