Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Position: (GRCh38/hg38):Chr6:41158716 A>T
Position: (GRCh37/hg19):Chr6:41126454 A>T
dbSNP ID: rs200820365
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGC to TGC
Reference Isoform: TREM2 Isoform 2 (219 aa)
Genomic Region: Exon 4 of transcript variant 2

Findings

The rs200820365 variant is present 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 serine-to-cysteine substitution at amino acid 183.

The S183C variant initially was reported in a case-control study of Han Chinese, in which it did not associate with Alzheimer’s disease: 12 of 988 AD patients and six of 1354 controls carried the variant (p = 0.14) (Jiang et al., 2016).

Subsequently, the variant was found in three individuals from two unrelated Chinese families (Zhang et al., 2020). (These families were among 75 selected for targeted sequencing of neurodegeneration-related genes—families containing at least two AD cases in two generations, without mutations in APP, PSEN1, or PSEN2.) This same study then asked whether the S183C variant associated with disease in a Chinese cohort of 506 sporadic AD cases and 498 controls and found that it did not. Finally, to increase the sample size, the frequency of the variant in these sporadic AD cases was compared with the frequency in East Asians in the ExAC database (N = 8628); in this instance, the variant was found to be significantly associated with AD risk.

Neuropathology

No data.

Biological Effect

The biological effect of the serine-to-cysteine substitution has not been tested directly. However, the variant was predicted to be tolerated by SIFT but possibly damaging by PolyPhen-2, and it was classified as a polymorphism by Mutation Taster (Zhang et al., 2020).

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References

Paper Citations

1. Jiang T, Tan L, Chen Q, Tan MS, Zhou JS, Zhu XC, Lu H, Wang HF, Zhang YD, Yu JT. A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging. 2016 Jun;42:217.e1-3. Epub 2016 Mar 3 PubMed.
2. Zhang W, Jiao B, Xiao T, Liu X, Liao X, Xiao X, Guo L, Yuan Z, Yan X, Tang B, Shen L. Association of rare variants in neurodegenerative genes with familial Alzheimer's disease. Ann Clin Transl Neurol. 2020 Oct;7(10):1985-1995. Epub 2020 Sep 17 PubMed.

Further Reading

No Available Further Reading