Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Late-onset
Reference Assembly: GRCh37/hg19
Position: Chr14:73653604 T>C
dbSNP ID: rs63750771
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTC to TCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6


This mutation was found in a screen for PSEN1 mutations in an Italian family spanning four generations with several members suffering from late-onset AD. The mutation was identified in only one of three living patients with AD (and two asymptomatic sons of the proband who were younger than the mean age of AD onset). The mutation is unlikely to be a common, non-pathogenic polymorphism of this population because it was absent from 60 individuals with sporadic late-onset AD and 40 normal controls. It was also absent from the gnomAD variant database (gnomAD v2.1.1, June 2021). The authors hypothesize the mutation may be a de novo mutation in the proband, or express incomplete penetrance, causing disease only when combined with other genetic or environmental factors.

Indeed, the authors identified several factors that might affect disease expression in this family. For example, both affected and unaffected individuals in the second generation who were genotyped, including all three patients with AD, carried at least one APOE4 allele. Mean age at onset for the two individuals who were homozygotes was 61, whereas the heterozygote developed symptoms at age 70. In addition, a GG/TT substitution was found in the 3' end of PSEN1 intron 6 of all relatives genotyped in the second and third generations, including affected and unaffected individuals. Levels of estrogen, a hormone reported to be neuroprotective, may also affect disease expression. All affected members of this family were women who experienced precocious menopause without receiving estrogen-replacement therapy.

Biological Effect

Expression of the PSEN1 I439V variant in mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2 and expressing APP695 (N2A695) resulted in Ab4 and Ab42 levels similar to those of cells expressing wild-type PSEN1 (Hsu et al., 2020). The Aβ42/Aβ40 ratio was also unaffected. These authors classified the variant as not pathogenic.

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021).

Last Updated: 10 Sep 2021


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Paper Citations

  1. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  2. . 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. . F175S change and a novel polymorphism in presenilin-1 gene in late-onset familial Alzheimer's disease. Eur Neurol. 2002;47(4):209-13. PubMed.

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