Mutations

TREM2 S162R

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity, Frontotemporal Dementia : Unclear Pathogenicity
Position: (GRCh38/hg38):Chr6:41159063 C>G
Position: (GRCh37/hg19):Chr6:41126801 C>G
dbSNP ID: rs371702633
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGC to AGG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 4

Findings

In a Caucasian cohort from the Alzheimer’s Disease Sequencing Project (2927 AD, 2633 controls), the S162R variant was found with a minor allele frequency of 0.00034 in Alzheimer’s patients but was not seen in cognitively healthy controls (Sirkis et al., 2016). In a Belgian study, the variant was found in one of 1216 AD patients, and in none of 359 FTD patients or 1094 controls (Cuyvers et al., 2014).

Neuropathology

No data.

Biological Effect

The serine-to-arginine substitution at amino acid 162 was predicted by Polyphen2 to be benign, by SIFT to be tolerated, and by SNPs&Go to be neutral (Cuyvers et al., 2014). The variant exhibits normal protein maturation when heterologously expressed in HEK293 cells (Sirkis et al., 2016).

Last Updated: 07 Feb 2018

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References

Paper Citations

  1. Sirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EM, Wang Q, Karydas A, Miller ZA, Miller BL, Coppola G, Yokoyama JS. Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun. 2016 Sep 2;4(1):98. PubMed.
  2. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G, Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Cruts M, Sleegers K, BELNEU consortium. Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. Epub 2013 Oct 9 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G, Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Cruts M, Sleegers K, BELNEU consortium. Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. Epub 2013 Oct 9 PubMed.
  2. Sirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EM, Wang Q, Karydas A, Miller ZA, Miller BL, Coppola G, Yokoyama JS. Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun. 2016 Sep 2;4(1):98. PubMed.

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