Mutations

TREM2

TREM2 encodes Triggering Receptor Expressed on Myeloid Cells 2, a transmembrane receptor that modulates microglial activity and survival. TREM2 variants cause Nasu-Hakola disease (NHD), a rare autosomal recessive early-onset dementia, and may modify the risk of developing Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).​

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Search Results

TREM2 (68)

Mutation Pathogenicity DNA Change Expected RNA | Protein Consequence Coding/Non-Coding Genomic Region Neuropathology Biological Effect Primary
Papers
rs9357347
 AD : Possible Risk Modifier Substitution Non-Coding Intergenic - TREM locus Unknown. Predicted to influence transcription factor binding; 6 percent increase in expression of TREM2 and TREML1 in temporal cortex. Carrasquillo et al., 2017
c.-5030G>C
(rs7759295)		 AD : Unclear Pathogenicity Substitution Non-Coding Upstream This variant was associated with a higher burden of neurofibrillary tangles in subjects from three prospective cohort studies, but not with amyloid plaques, amyloid angiopathy, Lewy body pathology, terminally activated microglia, or cerebral infarcts. Unknown. Replogle et al., 2015
c.-2986T>C
(rs7748777)		 AD : Possible Risk Modifier Substitution Non-Coding Upstream Unknown. Unknown. Wang et al., 2015
E14Ter
 NHD : Pathogenic Substitution Substitution | Nonsense Coding Exon 1 Unknown. Premature truncation codon; no transcripts detected. Paloneva et al., 2003
c.40+3 delAGG
 FTD : Pathogenic Deletion Splicing Alteration | Non-Coding Intron 1 Unknown; MRI showed brain atrophy, including thinning of the corpus callosum. Reduction in the level of TREM2 transcripts. Chouery et al., 2008
S16F
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Unknown. Sirkis et al., 2016
G17E
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted benign by Polyphen-2, tolerated by SIFT, neutral by SNPs&Go. Cuyvers et al., 2014
V27M
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Normal protein maturation in HEK293 cells. Sirkis et al., 2016
A28V
 AD : Benign, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Normal protein maturation and increased cell-surface expression in HEK293 cells. Sims et al., 2017
S31F
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Normal protein maturation, decreased total and cell-surface expression in HEK293 cells. Sirkis et al., 2016
Q33Ter
 NHD : Pathogenic, FTD : Pathogenic, AD : Possible Risk Modifier Substitution Substitution | Nonsense Coding Exon 2 Unknown for homozygous carriers; MRI showed cerebral atrophy. Heterozygous AD patient showed typical AD pathology. Loss of TREM2 expression. Soragna et al., 2003;
Guerreiro et al., 2013
Y38C
 FTD : Pathogenic Substitution Substitution | Missense Coding Exon 2 Unknown; MRI shows cortical atrophy and white matter abnormalities. Alters post-translational processing of TREM2, ligand binding, and TREM2-mediated phagocytosis. Guerreiro et al., 2013
D39G
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted to be benign by Polyphen-2, tolerated by SIFT, and neutral by SNPs&Go. Cuyvers et al., 2014
D39E
 AD : Benign, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Not applicable. Predicted to be possibly damaging by Polyphen-2, but to be tolerated by SIFT and neutral by SNPs&Go. Sims et al., 2017
H43Y
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted benign by PolyPhen2. Pottier et al., 2013
W44Ter
 NHD : Pathogenic Substitution Substitution | Nonsense Coding Exon 2 Brain atrophy reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains. Paloneva et al., 2002
G45E
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Unknown. Jonsson et al., 2013
R47C
 AD : Unclear Pathogenicity, FTD : Pathogenic Substitution Substitution | Missense Coding Exon 2 Unknown, but MRI showed symmetric frontal and temporal lobe atrophy in homozygous carrier. Normal protein maturation, decreased total and cell-surface expression in HEK293 cells. Sirkis et al., 2016;
Ng et al., 2018
R47H
 AD : Risk Modifier, FTD : Possible Risk Modifier, PD : Possible Risk Modifier, ALS : Possible Risk Modifier Substitution Substitution | Missense Coding Exon 2 AD patients heterozygous for the R47H variant:  generally typical AD pathology, but subtle differences compared to non-carriers, including decreased microglial coverage of amyloid plaques and accumulation of phagosomes in microglia. Decreased ligand binding to TREM2 and impaired TREM2-mediated activation. Guerreiro et al., 2013;
Jonsson et al., 2013
W50C
 NHD : Pathogenic Substitution Substitution | Missense Coding Exon 2 Unknown; imaging showed brain atrophy, diffuse white-matter hyperintensities, thinning of the corpus callosum, and basal ganglia calcification. Unknown; predicted to be harmful in silico by Polyphen-2 and SIFT. Dardiotis et al., 2017
R52C
 FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 MRI showed diffuse brain atrophy and ventricular enlargement. Unknown. Soares et al., 2020
R52H
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Lower cell-surface expression than wild-type TREM2 when co-expressed with its adaptor protein DAP12 in a reporter cell line, but activation by phospholipids similar in cells expressing R52H and wild-type TREM2. Jin et al., 2014
G58A
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted by Polyphen2 to be probably damaging, by SIFT to be tolerated, and by SNPs&Go to be neutral. Cuyvers et al., 2014
R62C
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Lower cell-surface expression than wild-type TREM2 when co-expressed with its adaptor protein DAP12 in a reporter cell line; activation by lipid ligands reduced in cells expressing R62C compared with cells expressing wild-type TREM2. Pottier et al., 2013;
Song et al., 2017
R62H
 AD : Risk Modifier Substitution Substitution | Missense Coding Exon 2 AD patients heterozygous for the R62H variant: decreased microglial coverage of amyloid plaques and increased accumulation of phagosomes in microglia, compared to non-carriers. Decreased ligand binding to TREM2 and impaired TREM2-mediated activation. Jin et al., 2014;
Sims et al., 2017
T66M
 FTD : Pathogenic Substitution Substitution | Missense Coding Exon 2 Unknown; MRI showed frontal lobe atrophy, ventricular enlargement, and white-matter abnormalities in one homozygous carrier, and frontal and parietal lobe atrophy in two other homozygous carriers. Greatly decreased cell-surface expression and shedding of sTREM2, reduced ligand binding, and impaired phagocytosis. Guerreiro et al., 2013
N68K
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted  benign by PolyPhen2; apparently normal protein folding. Guerreiro et al., 2013
L72V
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted by SIFT to be tolerated but by Polyphen2 to be damaging. Ghani et al., 2016
W78Ter
 NHD : Pathogenic Substitution Substitution | Missense Coding Exon 2 Brain atrophy has been reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains. Paloneva et al., 2002
D86V
 FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown; MRI of a patient carrying both the Y38C and D86V variants, showed cortical atrophy, thinning of the corpus callosum, periventricular white-matter abnormalities,ventricular enlargement and probable globus pallidus calcification. Decreased cell-surface expression and defective N-linked glycosylation. Guerreiro et al., 2013
D87N
 AD : Possible Risk Modifier Substitution Substitution | Missense Coding Exon 2 Typical AD pathology in single described case (Braak Stage 6). Decreased binding to lipoproteins in cell-free assay, but increased ligand-stimulated activation in reporter cell line. Guerreiro et al., 2013
G90Vfs
 NHD : Pathogenic Deletion Deletion | Frame Shift Coding Exon 2 Unknown; MRI showed leukoencephalopathy and cerebral atrophy. Unknown. Klünemann et al., 2005
T96K
 FTD : Possible Risk Modifier Substitution Substitution | Missense Coding Exon 2 Unknown; carriers of the T96K/W191X/L211P variants have lower levels of sTREM2 in CSF, compared with noncarriers. Increased binding to cell-derived ligands and increased activation by phospholipids seen in reporter cell line. Thelen et al., 2014
R98W
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted to be probably damaging by PolyPhen2. Guerreiro et al., 2013
A105Rfs
 NHD : Pathogenic Substitution Substitution | Frame Shift Coding Exon 2 Unknown; imaging showed cerebral atrophy, leukoencephalopathy, thinning of the corpus callosum, basal ganglia calcification. Unknown. Klünemann et al., 2005
A105T
 FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted to be neutral by SIFT and by the PolyPhen 2 HumVar algorithm, but to be possibly damaging by PolyPhen2 HumDiv. Thelen et al., 2014
A105V
 AD : Benign Substitution Substitution | Missense Coding Exon 2 Unknown. Unknown. Sims et al., 2017;
Jin et al., 2015
S116C
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Cell-surface expression similar to that of wild-type TREM2 heterologously expressed in HEK293 cells. Borroni et al., 2014
V126G
 NHD : Pathogenic Substitution Substitution | Missense Coding Exon 2 Unknown; MRI showed leukoencephalopathy with sparing of arcuate fibers, cerebral atrophy, and thinning of the corpus callosum. Poor cell-surface expression and defective for N-linked glycosylation in the Golgi. Klünemann et al., 2005
A130S
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Normal protein maturation when heterologously expressed in HEK293 cells. Sirkis et al., 2016
A130V
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 2 Unknown. Predicted by SIFT to be damaging. Jiao et al., 2014
c.391+1G>A
 FTD : Pathogenic Substitution Splicing Alteration | Non-Coding Intron 2 Magnetic resonance imaging revealed cortical atrophy, ventricular enlargement, pronounced thinning of the corpus callosum, and diffuse white-matter hyperintensites. Calcification of the globus pallidus was observed by computed tomography. In heterologous expression systems, this variant was found to cause abnormal splicing (i.e., retention of intron 2). Although TREM2 protein levels were not assayed in these in vitro studies, the lack of soluble TREM2 in the proband’s CSF suggests abnormal protein expression or processing. Li et al., 2019
c.392-352T>C
(rs7748513)		 AD : Possible Risk Modifier Substitution Substitution | Non-Coding Intron 2 Unknown. Unknown. Reitz et al., 2013
D131D
 AD : Benign Substitution Substitution | Silent Coding Exon 3 Not applicable. Unknown. Sims et al., 2017
L133L
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Silent Coding Exon 3 Unknown. Unknown. Cuyvers et al., 2014
D134G
 NHD : Pathogenic, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 3 Brain atrophy. Unknown. Paloneva et al., 2002
R136W
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 3 Unknown. Normal protein maturation, decreased total and cell-surface expression in HEK 293 cells; when stimulated by phospholipids, reporter cells expressing the R136W variant responded similarly to cells expressing wild-type TREM2. Jin et al., 2014
R136Q
 AD : Benign, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 3 Unknown. Normal protein maturation, slightly reduced cell-surface expression in HEK293 cells. Sims et al., 2017
G145W
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 3 Unknown, but MRI of proband showed diffuse cortical atrophy. Leads to a change in protein conformation (shortening of the intrinsically disordered region between the immunoglobulin-like and transmembrane domains), and reduces cellular response to activation of the TREM2/DAP12 signaling complex. Karsak et al., 2020
E151K
 AD : Benign Substitution Substitution | Missense Coding Exon 3 Unknown. Normal protein maturation but reduction in overall expression in HEK 293 cells; when stimulated by phospholipids, reporter cells expressing the E151K variant responded similarly to cells expressing wild-type TREM2. Jonsson et al., 2013;
Sims et al., 2017
H157Y
 AD : Possible Risk Modifier Substitution Substitution | Missense Coding Exon 3 Unknown. Increases shedding of sTREM2. Reduces activation in response to phospholipid ligands and decreases phagocytosis. Jiang et al., 2016;
Jiang et al., 2016;
Sims et al., 2017
c.482+1G>A
 FTD : Pathogenic Substitution Splicing Alteration | Non-Coding Intron 3 Unknown; MRI showed periventricular white-matter hyperintensities, enlargement of the lateral ventricles, and thinning of the corpus callosum. Unknown. Chee et al., 2017
c.482+2T>C
 NHD : Pathogenic, FTD : Unclear Pathogenicity Substitution Splicing Alteration | Deletion Non-Coding Intron 3 Unknown; imaging showed brain atrophy, basal ganglia calcification, and hypoperfusion in the frontotemporal cortex of NHD patient. Exon 3 skipping, with deletion of exons 2 and/or 4, and the presence of premature or original stop codons; two truncated TREM2 protein products detected, which are likely to be nonfunctional. Paloneva et al., 2002;
Numasawa et al., 2011
S162R
 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 Unknown. Normal protein maturation in HEK293 cells. Cuyvers et al., 2014;
Sirkis et al., 2016
K186N
 NHD : Pathogenic Substitution Substitution | Missense Coding Exon 4 Brain atrophy. Predicted to result in defects in signal transduction.

 

  		Paloneva et al., 2002
A192T
 AD : Benign Substitution Substitution | Missense Coding Exon 4 Unknown. Predicted to be possibly damaging by Polyphen2. Sims et al., 2017;
Jiang et al., 2016
A196T
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 Unknown. Unknown. Sirkis et al., 2016
W198Ter
 FTD : Pathogenic Substitution Substitution | Missense Coding Exon 4 Unknown; frontal lobe atrophy seen on MRI. Premature truncation. Giraldo et al., 2013
L211P
 AD : Possible Risk Modifier, FTD : Possible Risk Modifier Substitution Substitution | Missense Coding Exon 4 Unknown; lower levels of sTREM2 in CSF of T96K/W191X/L211P carriers. Predicted tolerated in silico by SIFT and benign by PolyPhen-2. Jin et al., 2015
H215Q
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 Unknown. Unknown. Jin et al., 2014
T223I
 AD : Benign, FTD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 Unknown. Predicted by Polyphen2 to be benign, by SIFT to be tolerated and by SNPs&Go to be neutral; normal protein maturation in HEK293 cells. Sims et al., 2017
S183C
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 of transcript variant 2 Unknown. Predicted to be tolerated by SIFT but possibly damaging by PolyPhen-2; classified as a polymorphism by Mutation Taster. Jiang et al., 2016;
Zhang et al., 2020
W191Ter
 AD : Unclear Pathogenicity Substitution Substitution | Nonsense Coding Exon 4 of transcript variant 2 Unknown. Unknown. Jin et al., 2015
c.*73G>A
(rs2234258)		 AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Substitution Substitution | Non-Coding Exon 5, 3' UTR Unknown. Unknown. Cuyvers et al., 2014
W200C
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 of transcript variant 2 Unknown. Predicted to be probably damaging by Polyphen2. Jiang et al., 2016
E202D
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 of transcript variant 2 Unknown. Unknown. Jin et al., 2014;
Jin et al., 2015
L205P
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 of transcript variant 2 Unknown. Predicted by SIFT to be damaging, but by Polyphen2 to be benign. Ghani et al., 2016
G219C
 AD : Unclear Pathogenicity Substitution Substitution | Missense Coding Exon 4 of transcript variant 2 Unknown. Predicted by SIFT to be damaging but by Polyphen2 to be benign. Ghani et al., 2016