NM_032638.5(GATA2):c.1113C>G (p.Asn371Lys) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001859359.4

Allele description [Variation Report for NM_032638.5(GATA2):c.1113C>G (p.Asn371Lys)]

NM_032638.5(GATA2):c.1113C>G (p.Asn371Lys)

Gene:

GATA2:GATA binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q21.3

Genomic location:

Preferred name:

NM_032638.5(GATA2):c.1113C>G (p.Asn371Lys)

HGVS:

NC_000003.12:g.128481849G>C
NG_029334.1:g.16339C>G
NM_001145661.2:c.1113C>G
NM_001145662.1:c.1071C>G
NM_032638.5:c.1113C>GMANE SELECT
NP_001139133.1:p.Asn371Lys
NP_001139134.1:p.Asn357Lys
NP_116027.2:p.Asn371Lys
LRG_295:g.16339C>G
NC_000003.11:g.128200692G>C

Protein change:

N357K

Links:

dbSNP: rs376003468

NCBI 1000 Genomes Browser:

rs376003468

Molecular consequence:

NM_001145661.2:c.1113C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001145662.1:c.1071C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_032638.5:c.1113C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deafness-lymphedema-leukemia syndrome
Synonyms:: Lymphedema, primary, with myelodysplasia; Emberger syndrome
Identifiers:: MONDO: MONDO:0013540; MedGen: C3279664; Orphanet: 3226; OMIM: 614038

Name:: Monocytopenia with susceptibility to infections
Synonyms:: MONOCYTOPENIA AND MYCOBACTERIAL INFECTION SYNDROME; MONOCYTOPENIA WITH SUSCEPTIBILITY TO MYCOBACTERIAL, FUNGAL, AND PAPILLOMAVIRUS INFECTIONS AND MYELODYSPLASIA; COMBINED IMMUNODEFICIENCY WITH SUSCEPTIBILITY TO MYCOBACTERIAL, VIRAL, AND FUNGAL INFECTIONS; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013607; MedGen: C3280030; Orphanet: 228423; OMIM: 614172

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Mus musculus chaperone, ABC1 activity of bc1 complex like (S. pombe) (Cabc1), mR...
Mus musculus chaperone, ABC1 activity of bc1 complex like (S. pombe) (Cabc1), mRNA
gi|12963648|ref|NM_023341.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002284980	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21670465, 24077845, 26702063, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002284980

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 5, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome.

Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, Frucht DM, Vinh DC, Auth RD, Freeman AF, Olivier KN, Uzel G, Zerbe CS, Spalding C, Pittaluga S, Raffeld M, Kuhns DB, Ding L, Paulson ML, Marciano BE, Gea-Banacloche JC, Orange JS, et al.

Blood. 2011 Sep 8;118(10):2653-5. doi: 10.1182/blood-2011-05-356352. Epub 2011 Jun 13.

PubMed [citation]

PMID:: 21670465
PMCID:: PMC3172785

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation.

West RR, Hsu AP, Holland SM, Cuellar-Rodriguez J, Hickstein DD.

Haematologica. 2014 Feb;99(2):276-81. doi: 10.3324/haematol.2013.090217. Epub 2013 Sep 27.

PubMed [citation]

PMID:: 24077845
PMCID:: PMC3912957

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002284980.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 371 of the GATA2 protein (p.Asn371Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GATA2-related conditions and/or myelodysplastic syndrome (PMID: 21670465, 24077845, 26702063; Invitae). ClinVar contains an entry for this variant (Variation ID: 1184162). 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. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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