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