Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685908 A>G
dbSNP ID: rs63750249
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was found in two sisters affected by early onset Alzheimer's disease (Rogaeva et al., 2001). They inherited the mutation from their mother, who was asymptomatic at age 55. Importantly, both sisters also carried PSEN1 I143T, a variant which has been classified as pathogenic and which they inherited from their father. Information related to his clinical history was not reported. Both sisters developed symptoms before age 35.

The variant is absent from the EVS and ExAC variant databases (Hsu et al., 2020).



Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a moderate increase in production of Aβ40 and Aβ42 compared with wildtype PSEN1, without altering the Aβ42/Aβ40 ratio (Sun et al., 2017). Similarly, the Aβ42/Aβ40 ratio remained unchanged in mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2 and expressing APP695 (N2A695) and the PSEN1 I439V variant (Hsu et al., 2020). In this latter assay, Aβ42, but not Aβ40, secretion was increased.

I439 is conserved between PSEN1 and PSEN2 and, although some silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Hsu et al., 2020Xiao 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). Hsu and colleagues classified I439V as probably pathogenic.

Last Updated: 22 Sep 2021


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Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 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.

Other Citations

  1. I143T

External Citations

  1. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position


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