Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637703 G>T
dbSNP ID: rs63750601
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This mutation was first identified in a Japanese family. The reported pedigree consisted of four affected family members over three generations. All affected individuals had early onset Alzheimer’s disease, with a mean age at onset of 52.5 ± 5.07 years (range: 49 to 60 years). The mutation was found in three affected carriers and three at-risk individuals who had yet to reach the mean age at onset. Moreover, it was absent from several unaffected family members who were past the age of onset, and from 100 non-demented controls (Kamino et al., 1996). It was also absent from the gnomAD variant database (May 2021).

The mutation was also found in two siblings from Malaysia with early onset AD (Giau et al., 2019). Both individuals had symptoms that began at age 40. In addition to memory loss, the patients experienced apathy and withdrawal. Both patients had an APOE3/APOE4 genotype.



Biological Effect

In vitro studies revealed a robust decrease in Aβ42 and Aβ40 production, as well as drastically reduced autoproteolytic endopeptidase activity (Brunkan et al., 2005; Sun et al., 2017). In cultured COS-1 cells, the Aβ42/Aβ40 ratio was increased two-fold (Kamino et al., 1996).

Although several in silico algorithms predicted this variant is damaging (Xiao et al., 2021), at least one did not (Giau et al., 2019), and the CADD-PHRED tool, which integrates diverse information, gave it a low deleteriousness score below 20 (CADD v.1.6, Sep 2021).

Last Updated: 27 Sep 2021


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Paper Citations

  1. . Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.
  2. . APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int J Mol Sci. 2019 Sep 25;20(19) PubMed.
  3. . Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity. J Neurochem. 2005 Sep;94(5):1315-28. 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 variant database
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.


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