Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640302 G>A
dbSNP ID: rs63750378
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAG to AAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was found in a Japanese family with four members affected by AD, spanning three generations (Yasuda et al., 1999). The proband presented with severe amnesia, disorientation in time and place, and word-finding difficulty at age 57, with a one-year history of progressive memory impairment and personality changes. His brother, who also carried the mutation, had similar symptoms starting at age 62 (Yasuda et al., 1999). 

Although the variant was absent from 100 healthy controls and 104 patients with sporadic AD, it was found in the gnomAD variant database with an allele count of three and a frequency of 0.0011 percent, and was predicted to most likely have reduced penetrance (Koriath et al., 2018).

Neuropathological data are unavailable. However, in the proband and his brother, MRI showed atrophy in the bilateral medial temporal lobes, and PET demonstrated hypoperfusion in the bilateral temporal and parietal lobes (Yasuda et al., 1999).

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 and Aβ42 production, and an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). The site of the mutation is not conserved between PSEN1 and PSEN2.

Last Updated: 26 May 2021


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Paper Citations

  1. . A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2. Arch Neurol. 1999 Jan;56(1):65-9. PubMed.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  3. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2. Arch Neurol. 1999 Jan;56(1):65-9. PubMed.


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