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TREM2 (64)

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).​

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
E14X
Nasu-Hakola Disease NHD : Pathogenic Unknown. Premature truncation codon; no transcripts detected.

rs386834143
Coding
Exon 1
Point, Nonsense
GAG to TAG
0 Paloneva et al., 2003
S16F
AD : Unclear Pathogenicity Unknown. Unknown.

rs777808487
Coding
Exon 2
Point, Missense
TCC to TTC
0 Sirkis et al., 2016
G17E
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted benign by Polyphen-2, tolerated by SIFT, neutral by SNPs&Go.

Coding
Exon 2
Point, Missense
GGA to GAA
0 Cuyvers et al., 2014
V27M
AD : Unclear Pathogenicity Unknown. Normal protein maturation in HEK293 cells.

rs768745050
Coding
Exon 2
Point, Missense
GTG to ATG
0 Sirkis et al., 2016
A28V
Primary Progressive Aphasia, Progressive Nonfluent Aphasia AD : Not Pathogenic, FTD : Unclear Pathogenicity Unknown. Normal protein maturation and increased cell-surface expression in HEK293 cells.

rs2234252
Coding
Exon 2
Point, Missense
GCG to GTG
0 Sims et al., 2017
S31F
AD : Unclear Pathogenicity Unknown. Normal protein maturation, decreased total and cell-surface expression in HEK293 cells.

rs746216516
Coding
Exon 2
Point, Missense
TCC to TTC
0 Sirkis et al., 2016
Q33X
Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Pathogenic, AD : Possible Risk Modifier Unknown for homozygous carriers; MRI showed cerebral atrophy. Heterozygous AD patient showed typical AD pathology. Loss of TREM2 expression.

rs104894002
Coding
Exon 2
Point, Nonsense
CAG to TAG
0 Soragna et al., 2003;
Guerreiro et al., 2013
Y38C
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI shows cortical atrophy and white matter abnormalities. Alters post-translational processing of TREM2, ligand binding, and TREM2-mediated phagocytosis.

rs797044603
Coding
Exon 2
Point, Missense
TAT to TGT
1 Guerreiro et al., 2013
D39E
AD : Not Pathogenic, FTD : Unclear Pathogenicity Not applicable. Predicted to be possibly damaging by Polyphen-2, but to be tolerated by SIFT and neutral by SNPs&Go.

rs200392967
Coding
Exon 2
Point, Missense
GAC to GAG
0 Sims et al., 2017
D39G
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted to be benign by Polyphen-2, tolerated by SIFT, and neutral by SNPs&Go.

Coding
Exon 2
Point, Missense
GAC to GGC
0 Cuyvers et al., 2014
H43Y
AD : Unclear Pathogenicity Unknown. Predicted benign by PolyPhen2.

Coding
Exon 2
Point, Missense
CAC to TAC
0 Pottier et al., 2013
W44X
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains.

rs104894001
Coding
Exon 2
Point, Nonsense
TGG to TGA
0 Paloneva et al., 2002
G45E
AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 2
Point, Missense
GGG to GAG
0 Jonsson et al., 2013
R47C
Behavioral variant FTD AD : Unclear Pathogenicity, FTD : Pathogenic 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.

rs753325601
Coding
Exon 2
Point, Missense
CGC to TGC
0 Sirkis et al., 2016;
Ng et al., 2018
R47H
Alzheimer's Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease AD : Risk Modifier, FTD : Possible Risk Modifier, PD : Possible Risk Modifier, ALS : Possible Risk Modifier 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.

rs75932628
Coding
Exon 2
Point, Missense
CGC to CAC
19 Guerreiro et al., 2013;
Jonsson et al., 2013
W50C
Nasu-Hakola Disease NHD : Pathogenic 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.

Coding
Exon 2
Point, Missense
GAG to TAG
0 Dardiotis et al., 2017
R52H
AD : Unclear Pathogenicity 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.

rs374851046
Coding
Exon 2
Point, Missense
CGC to CAC
0 Jin et al., 2014
G58A
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted by Polyphen2 to be probably damaging, by SIFT to be tolerated, and by SNPs&Go to be neutral.

Coding
Exon 2
Point, Missense
GGC to GCC
0 Cuyvers et al., 2014
R62C
AD : Unclear Pathogenicity 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.

rs201258314
Coding
Exon 2
Point, Missense
CGT to TGT
0 Pottier et al., 2013;
Song et al., 2017
R62H
Alzheimer's Disease AD : Risk Modifier 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.

rs143332484
Coding
Exon 2
Point, Missense
CGT to CAT
0 Jin et al., 2014;
Sims et al., 2017
T66M
Behavioral variant FTD FTD : Pathogenic 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.

rs201258663
Coding
Exon 2
Point, Missense
ACG to ATG
1 Guerreiro et al., 2013
N68K
AD : Unclear Pathogenicity Unknown. Predicted  benign by PolyPhen2; apparently normal protein folding.

rs753372932
Coding
Exon 2
Point, Missense
AAC to AAG
0 Guerreiro et al., 2013
L72V
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be tolerated but by Polyphen2 to be damaging.

rs765933093
Coding
Exon 2
Point, Missense
CTG to GTG
0 Ghani et al., 2016
W78X
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy has been reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains.

rs104893998
Coding
Exon 2
Point, Nonsense
TGG to TAG
0 Paloneva et al., 2002
D86V
Frontotemporal Dementia FTD : Unclear Pathogenicity 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.

Coding
Exon 2
Point, Missense
GAC to GTC
0 Guerreiro et al., 2013
D87N
Alzheimer's Disease AD : Possible Risk Modifier 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.

rs142232675
Coding
Exon 2
Point, Missense
GAT to AAT
0 Guerreiro et al., 2013
G90VfsX99
(TREM2 269delG)
Nasu-Hakola Disease NHD : Pathogenic Unknown; MRI showed leukoencephalopathy and cerebral atrophy. Unknown.

rs386834140
Coding
Exon 2
Deletion
GGT to GTG
0 Klünemann et al., 2005
T96K
Frontotemporal Dementia FTD : Possible Risk Modifier 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.

rs2234253
Coding
Exon 2
Point, Missense
ACG to AAG
0 Thelen et al., 2014
R98W
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted to be probably damaging by PolyPhen2.

rs147564421
Coding
Exon 2
Point, Missense
CGG to TGG
0 Guerreiro et al., 2013
A105RfsX84
(TREM2 313delG)
Nasu-Hakola Disease NHD : Pathogenic Unknown; imaging showed cerebral atrophy, leukoencephalopathy, thinning of the corpus callosum, basal ganglia calcification. Unknown.

rs386834141
Coding
Exon 2
Deletion
GCG to CGG
0 Klünemann et al., 2005
A105T
Primary Progressive Aphasia, Semantic Dementia FTD : Unclear Pathogenicity Unknown. Predicted to be neutral by SIFT and by the PolyPhen 2 HumVar algorithm, but to be possibly damaging by PolyPhen2 HumDiv.

Coding
Exon 2
Point, Missense
GCG to ACG
0 Thelen et al., 2014
A105V
AD : Not Pathogenic Unknown. Unknown.

rs145080901
Coding
Exon 2
Point, Missense
GCG to GTG
0 Sims et al., 2017;
Jin et al., 2015
S116C
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Cell-surface expression similar to that of wild-type TREM2 heterologously expressed in HEK293 cells.

Coding
Exon 2
Point, Missense
AGT to TGT
0 Borroni et al., 2014
V126G
Nasu-Hakola Disease NHD : Pathogenic 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.

rs121908402
Coding
Exon 2
Point, Missense
GTG to GGG
0 Klünemann et al., 2005
A130S
AD : Unclear Pathogenicity Unknown. Normal protein maturation when heterologously expressed in HEK293 cells.

Coding
Exon 2
Point, Missense
GCA to TCA
0 Sirkis et al., 2016
A130V
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be damaging.

rs201280312
Coding
Exon 2
Point, Missense
GCA to GTA
0 Jiao et al., 2014
D131D
AD : Not Pathogenic Not applicable. Unknown.

rs139607688
Coding
Exon 3
Point, Silent
GAC to GAT
0 Sims et al., 2017
L133L
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Unknown.

rs144250872
Coding
Exon 3
Point, Silent
CTG to CTT
0 Cuyvers et al., 2014
D134G
Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Unclear Pathogenicity Brain atrophy. Unknown.

rs28939079
Coding
Exon 3
Point, Missense
GAT to GGT
0 Paloneva et al., 2002
R136Q
Logopenic Progressive Aphasia AD : Not Pathogenic, FTD : Unclear Pathogenicity Unknown. Normal protein maturation, slightly reduced cell-surface expression in HEK293 cells.

rs149622783
Coding
Exon 3
Point, Missense
CGG to CAG
0 Sims et al., 2017
R136W
AD : Unclear Pathogenicity 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.

rs772641807
Coding
Exon 3
Point, Missense
CGG to TGG
0 Jin et al., 2014
E151K
AD : Not Pathogenic 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.

rs79011726
Coding
Exon 3
Point, Missense
GAG to AAG
0 Jonsson et al., 2013;
Sims et al., 2017
H157Y
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Increases shedding of sTREM2. Reduces activation in response to phospholipid ligands and decreases phagocytosis.

rs2234255
Coding
Exon 3
Point, Missense
CAC to TAC
0 Jiang et al., 2016;
Jiang et al., 2016;
Sims et al., 2017
S162R
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Normal protein maturation in HEK293 cells.

rs371702633
Coding
Exon 4
Point, Missense
AGC to AGG
0 Cuyvers et al., 2014;
Sirkis et al., 2016
S183C
AD : Unclear Pathogenicity Unknown. Predicted to be possibly damaging by PolyPhen2.

rs200820365
Coding
Exon 4 of transcript variant 2
Point, Missense
AGC to TGC
0 Jiang et al., 2016
K186N
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy. Predicted to result in defects in signal transduction.

 

 


rs28937876
Coding
Exon 4
Point, Missense
AAG to AAT
0 Paloneva et al., 2002
W191X
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs2234258
Coding
Exon 4 of transcript variant 2
Point, Nonsense
TGG to TAG
0 Jin et al., 2015
A192T
AD : Not Pathogenic Unknown. Predicted to be possibly damaging by Polyphen2.

rs150277350
Coding
Exon 4
Point, Missense
GCC to ACC
0 Sims et al., 2017;
Jiang et al., 2016
A196T
AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Missense
GCA to ACA
0 Sirkis et al., 2016
W198X
Behavioral variant FTD FTD : Pathogenic Unknown; frontal lobe atrophy seen on MRI. Premature truncation.

Coding
Exon 4
Point, Nonsense
TGG to TGA
0 Giraldo et al., 2013
W200C
AD : Unclear Pathogenicity Unknown. Predicted to be probably damaging by Polyphen2.

Coding
Exon 4 of transcript variant 2
Point, Missense
TGG to TGC
0 Jiang et al., 2016
E202D
AD : Unclear Pathogenicity Unknown. Unknown.

rs530314472
Coding
Exon 4 of transcript variant 2
Point, Missense
GAG to GAT
0 Jin et al., 2014;
Jin et al., 2015
L205P
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be damaging, but by Polyphen2 to be benign.

Coding
Exon 4 of transcript variant 2
Point, Missense
CTG to CCG
0 Ghani et al., 2016
L211P
Alzheimer's Disease, Frontotemporal Dementia AD : Possible Risk Modifier, FTD : Possible Risk Modifier Unknown; lower levels of sTREM2 in CSF of T96K/W191X/L211P carriers. Predicted tolerated in silico by SIFT and benign by PolyPhen-2.

rs2234256
Coding
Exon 4
Point, Missense
CTG to CCG
0 Jin et al., 2015
H215Q
AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Missense
CAT to CAG
0 Jin et al., 2014
G219C
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be damaging but by Polyphen2 to be benign.

rs768583708
Coding
Exon 4 of transcript variant 2
Point, Missense
GGT to TGT
0 Ghani et al., 2016
T223I
AD : Not Pathogenic, FTD : Unclear Pathogenicity 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.

rs138355759
Coding
Exon 4
Point, Missense
ACT to ATT
0 Sims et al., 2017
c.40+3 delAGG
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI showed brain atrophy, including thinning of the corpus callosum. Reduction in the level of TREM2 transcripts.

Non-Coding
Intron 1
Deletion
0 Chouery et al., 2008
c.482+1 G>A
Progressive Nonfluent Aphasia FTD : Pathogenic Unknown; MRI showed periventricular white-matter hyperintensities, enlargement of the lateral ventricles, and thinning of the corpus callosum. Unknown.

Non-Coding
Intron 3
Point
0 Chee et al., 2017
c.482+2 T>C
Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Unclear Pathogenicity 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.

rs386834144
Non-Coding
Intron 3
Point
0 Paloneva et al., 2002;
Numasawa et al., 2011
rs2234258
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Unknown.

rs2234258
Non-Coding
3' UTR
Point
0 Cuyvers et al., 2014
rs7748513
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Unknown.

rs7748513
Non-Coding
Intron 2
Point
0 Reitz et al., 2013
rs7748777
Alzheimer's Disease, ~ 1 year follow-up AD : Possible Risk Modifier Unknown. Unknown.

rs7748777
Non-Coding
Upstream
Point
0 Wang et al., 2015
rs9357347
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Predicted to influence transcription factor binding; 6 percent increase in expression of TREM2 and TREML1 in temporal cortex.

rs9357347
Non-Coding
Intergenic - TREM locus
Point
0 Carrasquillo et al., 2017