Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Reference Assembly: GRCh37/hg19
Position: Chr14:73640411 A>G
dbSNP ID: rs778630379
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was identified in a Korean woman with probable AD and a family history of the disease (Kim et al., 2020). Her symptoms, starting at age 59, included memory impairment, visuospatial dysfunction, aphasia, anxiety, and parkinsonism. Disease duration was five years.  Her APOE genotype was APOE3/APOE4.

The variant’s frequency in the gnomAD variant database was 0.000003977 with an allele count of one (gnomAD v2.1.1, Sep 2021). It was absent from 500 Korean controls (Kim et al., 2020).

Neuropathological data are unavailable, but MRI revealed diffuse parietal and hippocampal atrophy, and FDG-PET showed severe hypometabolism in bilateral frontoparieto-temporal cortex.

Biological Effect
The biological effect of this mutation is unknown, but the site is evolutionarily conserved (GERP score = 4.65) and several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Kim et al., 2020, Xiao et al., 2021).

In addition, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that Y159 appears to help stabilize the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019).

Kim et al. classified this mutation as probably pathogenic (Kim et al., 2020).

Last Updated: 10 Sep 2021


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.
  2. . 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.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.

Other mutations at this position

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