Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659536 A>C
dbSNP ID: rs63750888
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in three members of a Japanese-American family with a history of dementia onset in their early 40s (Edwards-Lee et al., 2006). Two individuals carrying the mutation had severe memory loss, but no signs of cognitive impairment in other domains. The third individual had a more characteristic AD profile, appearing to be at a more advanced stage of disease based on neuropsychological testing.

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

No neuropathological data are available. In the patient with the most advanced stage of disease, MRI showed diffuse brain atrophy, possibly age-related, with no abnormalities detected in the other two individuals (Edwards-Lee et al., 2006). Subsequent SPECT imaging of four mutation carriers revealed medial orbitofrontal and anterior temporal lobe hyperperfusion (Edwards-Lee et al., 2008).

Biological Effect
The production of Aβ42 and Aβ40 appears to be impaired in this mutant given that neither peptide was detectable in an in vitro assay using purified proteins to monitor cleavage of the APP-C99 substrate (Sun et al., 2017).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Last Updated: 11 Sep 2021


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Paper Citations

  1. . A presenilin-1 mutation (T245P) in transmembrane domain 6 causes early onset Alzheimer's disease. Neurosci Lett. 2006 May 8;398(3):251-2. PubMed.
  2. . Relative hyperperfusion by SPECT in a family with a presenilin 1 (T245P) mutation. Neurocase. 2008;15(1):53-9. PubMed.
  3. . 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.
  4. . 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A presenilin-1 mutation (T245P) in transmembrane domain 6 causes early onset Alzheimer's disease. Neurosci Lett. 2006 May 8;398(3):251-2. PubMed.


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