Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr6:41158691 G>A
Position: (GRCh37/hg19):Chr6:41126429 G>A
dbSNP ID: rs2234258
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TAG
Reference Isoform: TREM2 Isoform 2 (219 aa)
Genomic Region: Exon 4 of transcript variant 2

Findings

The W191Ter variant is present only in transcript variant 2, the shortest TREM2 transcript. This transcript encodes most of the extracellular domain, but lacks the coding region for the transmembrane domain; thus the predicted protein may be a soluble form of TREM2. The variant introduces a premature stop codon in place of tryptophan at amino acid 191.

A trend toward an association with increased risk for Alzheimer’s disease in African-Americans was found in one study (odds ratio: 1.35, p = 0.08) (Jin et al., 2015). However, the W191Ter variant is in linkage disequilibrium with three other TREM2 variants reported to be associated with AD: rs2234256 (L211P) (Jin et al., 2015; Piccio et al., 2016), rs2234253 (T96K) (Piccio et al., 2016), and c.392-352T>C (intron variant) (Reitz and Mayeux, 2013). When the analysis was adjusted for the presence of L211P, the association of W191Ter with AD risk was no longer significant (odds ratio: 1.10, p = 0.63). The W191Ter variant was not associated with AD risk in a cohort of North Americans of European descent (Jin et al., 2014).

Neuropathology

Levels of soluble TREM2 in CSF were significantly lower in carriers of the T96K/W191Ter/L211P variants than in noncarriers (all CDR=0) (Piccio et al., 2016).

Biological Effect

Unknown.

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References

Mutations Citations

1. TREM2 c.392-352T>C (rs7748513)

Paper Citations

1. Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, Lincoln S, Krishnan S, Kachadoorian M, Reitz C, Mayeux R, Wingo TS, Lah JJ, Levey AI, Murrell J, Hendrie H, Foroud T, Graff-Radford NR, Goate AM, Cruchaga C, Ertekin-Taner N. TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
2. Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
3. Reitz C, Mayeux R, Alzheimer’s Disease Genetics Consortium. TREM2 and neurodegenerative disease. N Engl J Med. 2013 Oct 17;369(16):1564-5. PubMed.
4. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, Bertelsen S, Goate AM, Cruchaga C. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. Epub 2014 Jun 4 PubMed.

Other Citations

1. L211P

Further Reading

No Available Further Reading