UniProtKB/Swiss-Prot Q9NZC2: Variant p.Arg47His

Triggering receptor expressed on myeloid cells 2
Gene: TREM2
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Variant information Variant position:

47 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

US The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Arginine (R) to Histidine (H) at position 47 (R47H, p.Arg47His). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties:

Change from large size and basic (R) to medium size and polar (H) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

0 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:

Lowest score: -4 (low probability of substitution).
Highest score: 11 (high probability of substitution).

More information can be found on the following page
Variant description:

Found in patients with late onset Alzheimer disease; uncertain significance; no effect on cell membrane localization; no effect on autophagy in microglia; no effect on phagocystosis, including amyloid plaque clearance by microglia; reduces ectodomain shedding caused by proteolytic cleavage by ADAM10, while also reducing the oligomerization of the extracellular domain after shedding; decreases binding to and uptake of LDL and CLU into cells; decreases binding to APOE, phospholipids and oligomeric APP cleavage product beta-amyloid peptide 42. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs75932628 [ dbSNP | Ensembl ]

Sequence information Variant position:

47 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

230 The length of the canonical sequence.
Location on the sequence:

VAGQSLQVSCPYDSMKHWGR R KAWCRQLGEKGPCQRVVSTH The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Residue conservation:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         VAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTH

Mouse                         MAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPCQRVVSTH

Sequence annotation in neighborhood:

The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:

Type: the type of sequence feature.
Positions: endpoints of the sequence feature.
Description: contains additional information about the feature.

Type	Positions	Description
Chain	19 – 230	Triggering receptor expressed on myeloid cells 2
Topological domain	19 – 174	Extracellular
Domain	29 – 112	Ig-like V-type
Binding site	67 – 67
Disulfide bond	36 – 110
Mutagenesis	36 – 36	C -> A. Loss of proteolytic cleavage by ADAM10 and ectodomain shedding. Decreases protein maturation and cell membrane localization.
Mutagenesis	48 – 48	K -> M. Loss of LDL, CLU and APOE binding.
Mutagenesis	60 – 60	C -> A. Loss of proteolytic cleavage by ADAM10 and ectodomain shedding. Decreases protein maturation and cell membrane localization.

Literature citations
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.
Kleinberger G.; Yamanishi Y.; Suarez-Calvet M.; Czirr E.; Lohmann E.; Cuyvers E.; Struyfs H.; Pettkus N.; Wenninger-Weinzierl A.; Mazaheri F.; Tahirovic S.; Lleo A.; Alcolea D.; Fortea J.; Willem M.; Lammich S.; Molinuevo J.L.; Sanchez-Valle R.; Antonell A.; Ramirez A.; Heneka M.T.; Sleegers K.; van der Zee J.; Martin J.J.; Engelborghs S.; Demirtas-Tatlidede A.; Zetterberg H.; Van Broeckhoven C.; Gurvit H.; Wyss-Coray T.; Hardy J.; Colonna M.; Haass C.;
Sci. Transl. Med. 6:243RA86-243RA86(2014)
Cited for: FUNCTION; SUBCELLULAR LOCATION; PROTEOLYTIC PROCESSING; CHARACTERIZATION OF VARIANTS CYS-38; HIS-47 AND MET-66; MUTAGENESIS OF CYS-36 AND CYS-60; Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.
Sirkis D.W.; Bonham L.W.; Aparicio R.E.; Geier E.G.; Ramos E.M.; Wang Q.; Karydas A.; Miller Z.A.; Miller B.L.; Coppola G.; Yokoyama J.S.;
Acta Neuropathol. Commun. 4:98-98(2016)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS MET-27; VAL-28; PHE-31; CYS-38; CYS-47; HIS-47; ASN-87; SER-130; GLN-136; TRP-136; LYS-151; ARG-162 AND ILE-223; TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.
Yeh F.L.; Wang Y.; Tom I.; Gonzalez L.C.; Sheng M.;
Neuron 91:328-340(2016)
Cited for: FUNCTION; TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; HIS-62; MET-66 AND ASN-87; MUTAGENESIS OF LYS-48; TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
Ulland T.K.; Song W.M.; Huang S.C.; Ulrich J.D.; Sergushichev A.; Beatty W.L.; Loboda A.A.; Zhou Y.; Cairns N.J.; Kambal A.; Loginicheva E.; Gilfillan S.; Cella M.; Virgin H.W.; Unanue E.R.; Wang Y.; Artyomov M.N.; Holtzman D.M.; Colonna M.;
Cell 170:649-663(2017)
Cited for: TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62; Human stem cell-derived monocytes and microglia-like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2.
Claes C.; Van Den Daele J.; Boon R.; Schouteden S.; Colombo A.; Monasor L.S.; Fiers M.; Ordovas L.; Nami F.; Bohrmann B.; Tahirovic S.; De Strooper B.; Verfaillie C.M.;
Alzheimers Dement. 15:453-464(2018)
Cited for: CHARACTERIZATION OF VARIANT HIS-47; TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function.
Zhao Y.; Wu X.; Li X.; Jiang L.L.; Gui X.; Liu Y.; Sun Y.; Zhu B.; Pina-Crespo J.C.; Zhang M.; Zhang N.; Chen X.; Bu G.; An Z.; Huang T.Y.; Xu H.;
Neuron 97:1023-1031(2018)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62; Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms.
Kober D.L.; Alexander-Brett J.M.; Karch C.M.; Cruchaga C.; Colonna M.; Holtzman M.J.; Brett T.J.;
Elife 5:E20391-E20391(2016)
Cited for: X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 19-133; DISULFIDE BONDS; SUBUNIT; SUBCELLULAR LOCATION; MUTAGENESIS OF ASN-68; ARG-76 AND ARG-77; GLYCOSYLATION AT ASN-79; CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; HIS-62; MET-66; ASN-87 AND LYS-96; CHARACTERIZATION OF VARIANT PLOSL2 GLY-126; Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2.
Sudom A.; Talreja S.; Danao J.; Bragg E.; Kegel R.; Min X.; Richardson J.; Zhang Z.; Sharkov N.; Marcora E.; Thibault S.; Bradley J.; Wood S.; Lim A.C.; Chen H.; Wang S.; Foltz I.N.; Sambashivan S.; Wang Z.;
J. Biol. Chem. 293:12634-12646(2018)
Cited for: X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 19-174 IN COMPLEX WITH PHOSPHATIDYLSERINE; PHOSPHOLIPID-BINDING; DISULFIDE BONDS; FUNCTION; SUBUNIT; GLYCOSYLATION AT ASN-20 AND ASN-79; CHARACTERIZATION OF VARIANT HIS-47; MUTAGENESIS OF ASN-20; Disease-associated mutations of TREM2 alter the processing of N-linked oligosaccharides in the Golgi apparatus.
Park J.S.; Ji I.J.; An H.J.; Kang M.J.; Kang S.W.; Kim D.H.; Yoon S.Y.;
Traffic 16:510-518(2015)
Cited for: CHARACTERIZATION OF VARIANT PLOSL2 33-GLN--THR-230 DEL; CHARACTERIZATION OF VARIANTS CYS-38; HIS-47 AND MET-66; SUBCELLULAR LOCATION;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.