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NM_138554.5(TLR4):c.896A>G (p.Asp299Gly) AND TLR4 POLYMORPHISM

Germline classification:
Benign (1 submission)
Last evaluated:
Sep 1, 2007
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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_138554.5(TLR4):c.896A>G (p.Asp299Gly)]

NM_138554.5(TLR4):c.896A>G (p.Asp299Gly)

TLR4:toll like receptor 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_138554.5(TLR4):c.896A>G (p.Asp299Gly)
  • NC_000009.12:g.117713024A>G
  • NG_011475.1:g.13843A>G
  • NG_011475.2:g.13622A>G
  • NM_003266.4:c.776A>G
  • NM_138554.5:c.896A>GMANE SELECT
  • NM_138557.3:c.296A>G
  • NP_003257.1:p.Asp259Gly
  • NP_612564.1:p.Asp299Gly
  • NP_612567.1:p.Asp99Gly
  • LRG_320t1:c.896A>G
  • LRG_320:g.13622A>G
  • LRG_320p1:p.Asp299Gly
  • NC_000009.11:g.120475302A>G
  • O00206:p.Asp299Gly
Protein change:
D259G; Asp299Gly
UniProtKB: O00206#VAR_012739; OMIM: 603030.0001; dbSNP: rs4986790
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_003266.4:c.776A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138554.5:c.896A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138557.3:c.296A>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
Increased function



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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
no assertion criteria provided
(Sep 1, 2007)
germlineliterature only

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

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



TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.

Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA.

Nat Genet. 2000 Jun;25(2):187-91.

PubMed [citation]

Toll-like receptor 4 polymorphisms and atherogenesis.

Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA.

N Engl J Med. 2002 Jul 18;347(3):185-92.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000027236.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (6)


Endotoxin Hyporesponsiveness

Arbour et al. (2000) showed that 2 common cosegregating missense mutations (asp299 to gly and thr399 to ile, 603030.0002) that affect the extracellular domain of the TLR4 receptor are associated with blunted response to inhaled lipopolysaccharide in humans. In transfection experiments, they found that the asp299-to-gly (D299G) mutation, but not the thr399-to-ile (T399I) mutation, interrupted TLR4-mediated LPS signaling. An A-to-G transition at nucleotide 896 of the TLR4 gene was responsible for the D299G amino acid change. Allele frequency of the 896G substitution was 6.6% in a population studied for airway responsiveness and 7.9% in a control population from Iowa. These findings indicated that the 2 populations were in Hardy-Weinberg equilibrium as to distribution of the TLR4 mutation. Findings demonstrated that the 896G substitution altered the ability of the host to respond to environmental stress; however, not all of the subjects who were hyporesponsive to LPS had mutations in TLR4, and not everyone with the TLR4 mutation was hyporesponsive to inhaled LPS.

In a study in Bruneck, Italy, Kiechl et al. (2002) found that out of 810 screened persons, 55 subjects had the D299G allele, with lower levels of certain proinflammatory cytokines, more susceptibility to severe bacterial infections, lower risk of carotid atherosclerosis, and a smaller intima-media thickness in the common carotid artery. The D299G allele was heterozygous in 53 and homozygous in 2 of the subjects. In 46 of these subjects, cosegregation with the T399I (603030.0002) polymorphism was observed, whereas 9 subjects had an isolated D299G polymorphism.

Colorectal Cancer, Susceptibility to

In a study of 89 Croatian patients with sporadic colorectal cancer (see 114500) and 88 sex- and age-matched Croatian controls, Boraska Jelavic et al. (2006) found that the gly299 allele of the TLR4 gene was more frequent in colorectal cancer patients than controls (p = 0.0269).

Macular Degeneration, Age-Related, 10, Susceptibility to

Zareparsi et al. (2005) examined the D299G and T399I (603030.0002) variants of TLR4 as contributors to susceptibility to age-related macular degeneration (ARMD10, 611488) in a sample of 667 unrelated Caucasian ARMD patients and 439 controls. Multiple logistic regression demonstrated an increased risk of ARMD in carriers of the G allele at TLR4 residue 299 (odds ratio = 2.65, P = 0.025), but lack of an independent effect by T399I variant. TLR4 D299G showed an additive effect on ARMD risk (odds ratio = 4.13, P = 0.002) with allelic variants of apolipoprotein E (APOE; 107741) and ATP-binding cassette transporter-1 (ABCA1; 600046), 2 genes involved in cholesterol efflux. The effect of TLR4, APOE, and ABCA1 variants on ARMD susceptibility was opposite to that of association with atherosclerosis risk.

Response to Anthracycline Therapy

Apetoh et al. (2007) analyzed the time to metastasis in a cohort of 280 patients with nonmetastatic breast cancer who were treated with anthracyclines after local surgery revealing lymph node involvement. The frequencies of heterozygous and homozygous germline D299G polymorphism (rs4986790) were 17.1% and 0.7%, respectively. Carriers of the polymorphism did not differ with respect to any classical prognostic factors from noncarriers. The frequency of metastasis by 5 years after surgery was statistically higher in the group carrying the D299G polymorphism (40% vs 26.5%). The Kaplan-Meier estimate of metastasis-free survival showed an overall significantly lower percentage of metastasis-free patients in the group of D299G carriers. Apetoh et al. (2007) found that the D299G SNP reduces the interaction between TLR4 and HMGB1 (163905) and abolishes the capacity of monocyte-derived dendritic cells to crosspresent dying melanoma cells to Mart1 (605513)-specific HLA-A2 (see 142800)-restricted cytotoxic T lymphocytes, a biologic property that depends on HMGB1 in wildtype monocyte-derived dendritic cells. Based on these and other findings, Apetoh et al. (2007) concluded that the D299G polymorphism in TLR4 may influence the immunologic component of anthracycline-based chemotherapy in human cancer. The authors stated that the D299G variant is found in 8 to 10% of Caucasians.

Myocardial Infarction

In Sicily, Balistreri et al. (2004) genotyped 105 young men with acute myocardial infarction, 127 male controls matched for age, and another control group of 55 very old men (mean age, 100 years) for the D299G polymorphism. They found significant differences among the 3 groups (p less than 0.001): the D299G allele was underrepresented in patients with acute myocardial infarction and overrepresented in very old men, with intermediate values in healthy young controls. After adjustment for risk factors, significant differences in allele frequency persisted between patients with acute myocardial infarction and very old men (p less than 0.002) and between young controls and very old controls (p less than 0.001).

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

Last Updated: Jun 23, 2024