Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Behavioral variant FTD
Reference Assembly: GRCh37/hg19
Position: Chr6:41129238 C>T
dbSNP ID: rs749358844
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2


This variant—in homozygosity—was identified in a Brazilian woman who began exhibiting signs of behavioral variant frontotemporal dementia at age 37. Among these signs were inability to plan and organize activities, socially inappropriate behaviors, carbohydrate cravings, memory loss, and insomnia. She also developed seizures. At age 39, cognitive testing confirmed executive and memory dysfunction, and MRI showed diffuse brain atrophy and ventricular enlargement. (By this time, the patient was unable to live independently.)

This patient had been diagnosed at age 7 with xeroderma pigmentosum (XP), a rare, autosomal-recessive disorder characterized by ultraviolet-induced skin cancers. Her particular subtype of XP, XPV, is associated with the POLH (DNA polymerase eta) gene, and she indeed was found to carry a homozygous protein-truncating mutation in POLH. She is the daughter of consanguineous parents, neither of whom showed signs of XP or FTD.

Although a quarter of XP patients also exhibit neurodegeneration, neurological dysfunction is not characteristic of the XPV subtype. By contrast, several homozygous mutations in TREM2 have been associated with FTD.

Two heterozygous carriers were found in gnomAD (v3) and none were found in the Exome Variant Server (databases searched 2020-10-05).

Last Updated: 07 Oct 2020


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Further Reading

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Protein Diagram

Primary Papers

  1. . Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia. Mol Genet Genomic Med. 2020 Nov;8(11):e1491. Epub 2020 Sep 16 PubMed.

Other mutations at this position


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