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TREM2 (68)

Mutation	Clinical Phenotype	Pathogenicity	Neuropathology	Biological Effect	Genomic Position	Genomic Region	Mutation Type Codon Change	Research Models	Primary Papers
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
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
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
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
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
rs2234258		AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity	Unknown.	Unknown.	rs2234258	Non-Coding 3' UTR	Point	0	Cuyvers et al., 2014
S183C		AD : Unclear Pathogenicity	Unknown.	Predicted to be tolerated by SIFT but possibly damaging by PolyPhen-2; classified as a polymorphism by Mutation Taster.	rs200820365	Coding Exon 4 of transcript variant 2	Point, Missense AGC to TGC	0	Jiang et al., 2016; Zhang et al., 2020
T223I		AD : Benign, 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
H215Q		AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 4	Point, Missense CAT to CAG	0	Jin et al., 2014
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
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
A196T		AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 4	Point, Missense GCA to ACA	0	Sirkis et al., 2016
A192T		AD : Benign	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
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
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
c.482+2T>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
c.482+1G>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
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
E151K		AD : Benign	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
G145W	Probable Alzheimer's Disease	AD : Unclear Pathogenicity	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.	rs766647311	Coding Exon 3	Point, Missense GGG to TGG	0	Karsak et al., 2020
R136Q	Primary Progressive Aphasia (Logopenic Variant)	AD : Benign, 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
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
L133L		AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity	Unknown.	Unknown.	rs144250872	Coding Exon 3	Point, Silent CTG to CTT	0	Cuyvers et al., 2014
D131D		AD : Benign	Not applicable.	Unknown.	rs139607688	Coding Exon 3	Point, Silent GAC to GAT	0	Sims et al., 2017
rs7748513	Alzheimer's Disease	AD : Possible Risk Modifier	Unknown.	Unknown.	rs7748513	Non-Coding Intron 2	Point	0	Reitz et al., 2013
c.391+1G>A	Frontotemporal Dementia	FTD : Pathogenic	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.		Non-Coding Intron 2	Point	0	Li et al., 2019
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
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
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
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
A105V		AD : Benign	Unknown.	Unknown.	rs145080901	Coding Exon 2	Point, Missense GCG to GTG	0	Sims et al., 2017; Jin et al., 2015
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
R52C	Behavioral variant FTD	FTD : Unclear Pathogenicity	MRI showed diffuse brain atrophy and ventricular enlargement.	Unknown.	rs749358844	Coding Exon 2	Point, Missense CGC to TGC	0	Soares et al., 2020
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	24	Guerreiro et al., 2013; 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
G45E		AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 2	Point, Missense GGG to GAG	0	Jonsson 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
H43Y		AD : Unclear Pathogenicity	Unknown.	Predicted benign by PolyPhen2.		Coding Exon 2	Point, Missense CAC to TAC	0	Pottier et al., 2013
D39E		AD : Benign, 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
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
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
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
A28V	Primary Progressive Aphasia, Progressive Nonfluent Aphasia	AD : Benign, 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
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
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
S16F		AD : Unclear Pathogenicity	Unknown.	Unknown.	rs777808487	Coding Exon 2	Point, Missense TCC to TTC	0	Sirkis et al., 2016
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
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
rs7748777	Alzheimer's Disease, ~ 1 year follow-up	AD : Possible Risk Modifier	Unknown.	Unknown.	rs7748777	Non-Coding Upstream	Point	0	Wang et al., 2015
rs7759295		AD : Unclear Pathogenicity	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.	rs7759295	Non-Coding Upstream	Point	0	Replogle 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
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