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NM_001982.4(ERBB3):c.4009G>A (p.Ala1337Thr) AND Erythroleukemia, familial, susceptibility to

Germline classification:
Likely pathogenic (2 submissions)
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_001982.4(ERBB3):c.4009G>A (p.Ala1337Thr)]

NM_001982.4(ERBB3):c.4009G>A (p.Ala1337Thr)

ERBB3:erb-b2 receptor tyrosine kinase 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001982.4(ERBB3):c.4009G>A (p.Ala1337Thr)
  • NC_000012.12:g.56102035G>A
  • NG_011529.1:g.26928G>A
  • NM_001982.4:c.4009G>AMANE SELECT
  • NP_001973.2:p.Ala1337Thr
  • NP_001973.2:p.Ala1337Thr
  • LRG_996t1:c.4009G>A
  • LRG_996:g.26928G>A
  • LRG_996p1:p.Ala1337Thr
  • NC_000012.11:g.56495819G>A
  • NM_001982.2:c.4009G>A
  • NM_001982.3:c.4009G>A
Protein change:
A1337T; ALA1337THR
OMIM: 190151.0002; dbSNP: rs755855285
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001982.4:c.4009G>A - missense variant - [Sequence Ontology: SO:0001583]


Erythroleukemia, familial, susceptibility to
DI GUGLIELMO DISEASE, FAMILIAL; Acute erythroleukemia, familial
MONDO: MONDO:0007573; MedGen: C5552985; Orphanet: 318; OMIM: 133180

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000298030Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
criteria provided, single submitter

(Submitter's publication)
Likely pathogenicgermlineresearch

PubMed (1)
[See all records that cite this PMID]

no assertion criteria provided
risk factor
(Sep 22, 2022)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyes2not providednot providednot providedyesresearch



A germline ERBB3 variant is a candidate for predisposition to erythroid MDS/erythroleukemia.

Braunstein EM, Li R, Sobreira N, Marosy B, Hetrick K, Doheny K, Gocke CD, Valle D, Brodsky RA, Cheng L.

Leukemia. 2016 Nov;30(11):2242-2245. doi: 10.1038/leu.2016.173. Epub 2016 Jun 15. No abstract available.

PubMed [citation]

Details of each submission

From Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine, SCV000298030.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providedyesresearch PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From OMIM, SCV000852036.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)


In 2 members of a family with familial erythroleukemia (FERLK; 133180), Braunstein et al. (2016) identified a heterozygous c.4009G-A transition in the ERBB3 gene, resulting in an ala1337-to-thr (A1337T) substitution at a conserved residue near the C terminus. The mutation, which was found by whole-exome sequencing, was not found in the Exome Variant Server, but was found at a low frequency in the ExAC database (7 of 119,654 alleles). The variant was also found in an asymptomatic 63-year-old family member, indicating incomplete penetrance, as well as in a female family member who died from metastatic breast cancer, but did not have leukemia. The family had a significant history of various solid tumors. Expression of the mutation into murine pro-B cells (BaF3) and human hematopoietic progenitor cells caused a growth advantage and resulted in increased cellular proliferation compared to wildtype. However, the increased proliferation was observed only in the presence of ERBB2 (164870), NRG1B (see 142445), and EPO (133170), indicating that the growth was dependent on ligand binding and heterodimerization. Analysis of the cell cycle under these conditions showed a decrease in the G1 phase and an increase in the S and G2/M phase in cells carrying the mutation compared to controls. These findings suggested that the A1337T variant overcomes a G1 phase cell cycle block. Cells carrying the mutation also showed a block in erythroid differentiation compared to controls.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 3, 2023