Submissions for variant NM_032638.5(GATA2):c.182C>T (p.Ala61Val)

gnomAD frequency: 0.00001  dbSNP: rs375349195

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234722	SCV000291137	uncertain significance	Deafness-lymphedema-leukemia syndrome; Monocytopenia with susceptibility to infections	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 61 of the GATA2 protein (p.Ala61Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 21892162). ClinVar contains an entry for this variant (Variation ID: 241721). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GATA2 protein function with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765713	SCV000897074	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
PreventionGenetics, part of Exact Sciences	RCV000984835	SCV001132719	uncertain significance	not provided	2017-07-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000984835	SCV001714710	uncertain significance	not provided	2021-02-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463686	SCV004198628	uncertain significance	Acute myeloid leukemia	2023-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000984835	SCV005331706	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with sporadic acute myeloid leukemia; however, it is unknown if the variant was germline or somatic (PMID: 21892162); This variant is associated with the following publications: (PMID: 21892162)
Ambry Genetics	RCV005338117	SCV006007570	uncertain significance	Inborn genetic diseases	2024-12-12	criteria provided, single submitter	clinical testing	The p.A61V variant (also known as c.182C>T), located in coding exon 1 of the GATA2 gene, results from a C to T substitution at nucleotide position 182. The alanine at codon 61 is replaced by valine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with GATA2 deficiency syndrome, but germline origin was not confirmed (Hahn CN et al. Nat Genet, 2011 Sep;43:1012-7; Hogg G et al. Cancer Genet, 2023 Nov;278-279:38-49). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.