Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
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). An unaffected, non-carrier sibling had normal cognition and no sign of amyloid accumulation as assessed by PET imaging at age 47.

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).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

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. Although one study reported in silico SIFT analysis predicted it to be tolerated, whereas Polyphen2 classified it as probably damaging (Benitez et al., 2013), another study, using additional in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) reported consistent results predicting this variant is damaging (Xiao et al., 2021).

Last Updated: 06 Aug 2021


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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.
  5. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

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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