Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685869 G>C
dbSNP ID: rs63751223
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCC to CCC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was first identified in a Scottish-Irish kindred with familial AD (Poorkaj et al., 1998). Six affected members had an average age of onset of 46 years. The mutation was found in both of the affected individuals tested, as well as in three at-risk individuals under the age of 51. It was absent from 200 controls. In a subsequent study of this kindred, five mutation carriers were identified, all of whom had either mild cognitive impairment (MCI) or AD, with ages of onset from 35-44 years (Klunk et al., 2007).

The mutation was also found in a 57-year-old without a clear family history of dementia in a screen of individuals with extreme CSF Aβ42, tau or phosphorylated tau levels (Benitez et al., 2013).

Neuropathology data are unavailable, but PiB-PET imaging of three mutation carriers with MCI and two with AD revealed amyloid deposition that differed from that observed in typical, sporadic AD (Klunk et al., 2007). Amyloid accumulation was particularly prominent in the striatum, and also observed in the neocortex and thalamus. The two individuals diagnosed with AD had lower PiB retention in frontal, temporoparietal, and precuneus cortices than most very mildly impaired sporadic AD patients.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it produces slightly lower amounts of Aβ40 and Aβ42 than the wildtype protein, without affecting the Aβ42/Aβ40 ratio (Sun et al., 2017). The mutation site is conserved in PSEN1, PSEN2, mouse PSEN1, and sel-12. In silico SIFT analysis predicted it to be tolerated, whereas Polyphen2 classified it as probably damaging (Benitez et al., 2013).

Last Updated: 19 Apr 2019


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Paper Citations

  1. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  2. . Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.
  3. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
  4. . 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.


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