Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653568 A>C
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was identified in a Korean woman with apparently sporadic early onset Alzheimer’s disease. She was a scientific researcher with 20 years of education, who began to experience behavioral and personality changes, namely emotional lability and neglect of personal hygiene, at the age of 33. She was originally diagnosed with depression, but three years later exhibited growing cognitive disturbance, including deficits in memory and executive functioning. As her disease progressed, she developed disorientation, nonfluent speech, Parkinsonian symptoms, apraxia, limb myoclonus, gait disturbance, and seizures.

Her family history was negative for dementia and other neurological disease. Her father died at age 50 from myocardial infarction and her mother was cognitively healthy at age 68. Her three older siblings were also unaffected. Segregation with disease could not be assessed due to lack of DNA from family members. The mutation was absent from 146 ethnically matched healthy controls (Kim et al., 2012) and from the gnomAD variant database (gnomAD v2.1.1, June 2021).


Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion protein were detected.

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP 695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016). Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Giau et al., 2019; Xiao et al., 2021). H163 is conserved between PSEN1 and PSEN2 (Hsu et al., 2020).

Last Updated: 10 Sep 2021


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Paper Citations

  1. . A novel PSEN1 H163P mutation in a patient with early-onset Alzheimer's disease: clinical, neuroimaging, and neuropathological findings. Neurosci Lett. 2012 Nov 21;530(2):109-14. PubMed.
  2. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  3. . APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int J Mol Sci. 2019 Sep 25;20(19) PubMed.
  4. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  5. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 H163P mutation in a patient with early-onset Alzheimer's disease: clinical, neuroimaging, and neuropathological findings. Neurosci Lett. 2012 Nov 21;530(2):109-14. PubMed.

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