Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73640293 G>A
dbSNP ID: rs63750800
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to AAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation has been reported in several families with a history of AD or dementia. One family of British/Irish decent, known as F121, had six affected family members over three generations. Onset of symptoms ranged from 32 to 39 years in this family, and a diagnosis of AD was confirmed by pathology in some family members (Hutton et al., 1996). It is unclear how many  members were genotyped in this family, but the P267S mutation was said to segregate with disease, and it was noted that the variant was not observed in unaffected, elderly family members or controls.

The details of the second family are limited, but the index patient was of Danish origin and developed symptoms at age 43 and had AD with spastic paraparesis. The mean age of onset in this family was reported as 44 years, ranging from 43 to 45 years; however, it was unclear how many individuals were affected. Segregation with disease could not be assessed due to lack of DNA from individuals other than the index patient (Lindquist et al., 2009).

The mutation has also been reported in two Korean women. In one case, the patient had progressive memory impairment beginning at 33 years of age (Li et al., 2018). By 38, she had global cognitive deficits, including impairments in verbal and visual memory, language, and visuospatial functions, with relative sparing of attention and frontal-executive function. She also had cerebellar dysfunction and was diagnosed with early onset dementia with spastic paraparesis. Of note, her grandmother developed dementia in her 70s and a cousin was diagnosed with late-onset cerebellar ataxia at age 54. Genetic testing of the patient for mutations linked to spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, Friedereich's ataxia, and Huntington's disease were negative. A second Korean woman carrying this mutation had AD and a family history of the disease (Kim et al., 2020). Her symptoms, which began at age 34, included memory impairment, visuospatial dysfunction, anomia, depression, apathy, abulia, and delusion. Motor symptoms also developed in this patient, including cerebellar ataxia, parkinsonism, and dystonia.

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).


Neuropathology consistent with AD was reported (Hutton et al., 1996). In the Korean patients, brain MRI revealed generalized cortical atrophy with atrophy in the bilateral medial temporal lobes and cerebellum in one case (Li et al., 2018), and mild, diffuse cortical atrophy with left hippocampal atrophy in the other (Kim et al., 2020). In this second patient, SPECT showed bilateral hypometabolism in the temporal lobes. Moreover, Aβ accumulation was found in the brains of both Korean patients using PiB PET imaging. In the first patient, the striatum, bilateral frontal lobes, posterior cingulate cortices, and precuneus, but not the cerebellum, were affected (Li et al., 2018).

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios.  Consistent with these findings, the mutant increased the Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695 (Murayama et al., 1999). Moreover, in an vitro assay using purified proteins, the mutation reduced the production of Aβ42, and nearly abrogated production of Aβ40, resulting in an approximately ten-fold increase in the Aβ42/Aβ40 ratio compared with wild-type PSEN1 (Sun et al., 2017). The effect of the mutation on total secreted Aβ remains unclear, however. Liu and colleagues reported reduced levels in their transfected cells (Liu et al., 2021), whereas a study using induced pluripotent stem cells (iPSCs) from a mutation carrier found increased extracellular accumulation of Aβ compared with control cells (Li et al., 2018). 

Of note, Liu and colleagues reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations, including E120K (Liu et al., 2021). Moreover, Li and co-workers reported increased levels of phosphorylated tau, mitochondrial abnormalities, and disrupted autophagy in patient iPSCs (Li et al., 2018).

The E120 site is evolutionarily conserved (GERP score = 4.74) and some in silico algorithms predicted the mutation is deleterious (Kim et al., 2020). Although Xiao and colleagues reported the results from multiple algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) as being inconsistent (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 : Pathogenic

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.


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


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.


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: 22 Feb 2022


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Paper Citations

  1. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  2. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.
  3. . iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia. Exp Neurobiol. 2018 Oct;27(5):350-364. Epub 2018 Oct 31 PubMed.
  4. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.
  5. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  6. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  7. . 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.
  8. . 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
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.

Other mutations at this position


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