Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73673096 A>C
dbSNP ID: rs63750298
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to CCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9


This mutation was identified in a French individual who was referred to a neurologist at age 33 for progressive motor impairment, including a spastic gait. Ten years later, he required a wheelchair and had severe dysarthria (difficulty speaking due to impairment of speech producing muscles). He had also developed dementia with prominent frontal lobe dysfunction. Segregation with disease could not be determined due to lack of DNA from relatives (Dumanchin et al., 2006).

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


Unknown, but MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding (Dumanchin et al., 2006).

Biological Effect

When expressed in HEK293 cells, this mutation increased Aβ40 and Aβ42 measured in the conditioned media. Although the concentrations of both peptides increased, the increase was greater for Aβ42 and the overall ratio of Aβ42/Aβ40 was significantly altered compared to cells expressing wild-type PSEN1 (Dumanchin et al., 2006). However, in an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, it generated dramatically less Aβ42 than the wild-type protein and abolished Aβ40 production (Sun et al., 2017).

This point mutation has also been shown to affect exon 9 splicing, leading to the exclusion of exon 9 in about 5 percent of transcripts (Dumanchin et al., 2006).

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: 29 Jul 2021


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Paper Citations

  1. . Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
  2. . 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.
  3. . 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. . Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.

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