Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640302 G>A
dbSNP ID: rs63750378
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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). In a subsequent study, a Japanese man with AD onset at 64 years of age was also reported as carrying the mutation (Islam et al., 2022).

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
The effects of this mutation on PSEN1 function remain uncertain, although they are likely damaging. An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a substantial decrease in Aβ40 and Aβ42 production, and an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). This increase was not observed in Chinese hamster ovary cells expressing the mutant protein, however, and levels of the APP intracellular domain (AICD), which reflects total Aβ production, as well as of Aβ38, Aβ40, and Aβ42 were similar to those of cells expressing wildtype PSEN1 (Kakuda et al., 2021). Importantly, however, production of the toxic Aβ43 peptide was increased. Analyses of the short peptides generated during the stepwise processing of APP by several AD-associated mutants suggested Aβ43 may sometimes be generated from Aβ48, rather than the canonical Aβ49 precursor. Interestingly, increased Aβ43 levels and increased production by this alternate pathway correlated with younger ages at disease onset.

In one carrier with an APOE3/3 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to a disruption of PSEN1’s proposed role in ApoE secretion.

Although the site of the mutation is not conserved between PSEN1 and PSEN2 (Yasuda et al., 1999) and one study reported that multiple in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).


Alzheimer's Disease : Uncertain Significance

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. E123K: Although observations were mixed, they suggested alterations with potentially damaging effects.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. E123K: Variant located at edge of mutational hot spot.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 07 Mar 2022


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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. . Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
  3. . 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.
  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.

Other Citations

  1. Kakuda et al., 2021

External Citations

  1. CADD v.1.6

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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