Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity, Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44039717 G>A
dbSNP ID: rs63750959
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 1


Initially associated with familial frontotemporal dementia, the clinical significance of the R5H variant is currently unclear, and it may be benign.

This variant was first identified in an 81-year-old man who was diagnosed with probable familial FTD. He started to experience amnesia and disorientation at age 75. He exhibited no personality changes, aggressive behavior, or parkinsonism, but became nearly mute and had rigidity of the upper extremities by the time of his death at age 81. An elder brother had died at age 86 with dementia, but DNA was not available for analysis and segregation with disease could not be shown. The mutation was absent in 54 controls (Hayashi et al., 2002).

The variant was subsequently found in two members of a Taiwanese family (Lin et al., 2017). The proband presented at age 63 with progressive non-fluent speech and impaired memory. Several months later, he developed apraxia, bradykinesia, rigidity, and stimulus-sensitive myoclonus in his right hand. Neuropsychological examination revealed impairments in attention, verbal memory, visuospatial abilities, and executive function, as well as transcortical motor aphasia. Asymmetric atrophy of the left frontal and temporal lobes were apparent on MRI, and SPECT showed hypometabolism in the left temporal and parietal cortices. He received a clinical diagnosis of frontotemporal dementia (progressive primary aphasia) with features of corticobasal syndrome. A sister of the proband, reported to suffer from persistent depressive disorder, also carried the MAPT R5H variant; at the age of 60, she did not exhibit signs of cognitive or motor dysfunction. The mother of the proband, who was diagnosed with ALS at age 60, was deceased and her DNA was not available for analysis. The variant was absent in two siblings, ages 57 and 62, who were normal upon neurological examination. Six family members from the third generation, aged 24–39 years, did not carry this variant and had normal neurological exams. The variant was not found among 997 Taiwanese individuals enrolled in the Taiwan Biobank.

The R5H variant has also been reported in a large-scale screening study of individuals and families affected by late-onset Alzheimer's disease. The variant was found in one European family; however, it did not segregate with disease. Only one of five mutation carriers had a diagnosis of AD, and a non-carrier had the disease as well. Therefore, this rare variant is unlikely to contribute significantly to AD pathogenesis (Cruchaga et al., 2012).

This variant was also detected in one out of 376 cognitively healthy subjects from the KORA-Age cohort, based in Germany. Limited information is available about this individual, but according to a description of the cohort as a whole, subjects were Caucasian and cognitively intact at age 65 or older (Schulte et al., 2015; Schulte et al., 2012).


CT scan of the proband with FTD showed severe atrophy of both temporal lobes. Postmortem analysis showed neuronal loss in the frontal and temporal lobes as well as widespread tau deposits predominantly in glia. Extensive deposition of Sarkosyl-insoluble tau filaments composed of 4-repeat (4R) tau, as well as straight tubules reminiscent of progressive supranuclear palsy, were also observed (Hayashi et al., 2002).

Biological Effect

This mutation reduces tau's ability to promote microtubule assembly and promotes fibril formation in vitro (Hayashi et al., 2002). PolyPhen2 predicted It was probably damaging in silico (Cruchaga et al., 2012).

Last Updated: 06 Apr 2018


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Paper Citations

  1. . Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol. 2002 Apr;51(4):525-30. PubMed.
  2. . Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review. BMC Neurol. 2017 Sep 18;17(1):186. PubMed.
  3. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. Epub 2012 Feb 1 PubMed.
  4. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  5. . Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease. Neurogenetics. 2012 Aug;13(3):281-5. Epub 2012 Jun 16 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol. 2002 Apr;51(4):525-30. PubMed.

Other mutations at this position


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