PSEN1 Q127_R128delinsG


Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640314_73640319 CAGAGA>G
Coding/Non-Coding: Coding
Mutation Type: Insertion/Deletion
Codon Change: CAGAGA to GGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation is a four base-pair deletion, including Q127 (CAG) and the first base pair of R128 (A), with an insertion of a G at the deletion site, resulting in the replacement of glutamine and arginine by a glycine (Hsu et al., 2018). It was found in an individual of a family in which four members were diagnosed with early-onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry. The proband had an age at symptomatic onset of 50 years, and the average age of onset in family members was 43 years. Only the proband's DNA was sequenced. The mutation was absent from two population-based exome sequencing databases, EVS and ExAC.


Biological Effect
Hsu et al. initially reported that neuroblastoma cells (N2A) stably expressing human APP secreted Aβ42 and Aβ40 at levels similar to those secreted by cells expressing wild-type PSEN1 (Hsu et al., 2018). However, in a subsequent paper, the researchers reported that the variant actually increased Aβ42 and decreased Aβ40 secretion in mouse neuroblastoma cells expressing this mutant on a PSEN1/PSEN2 null background, resulting in a nearly fivefold increase in the Aβ42/Aβ40 ratio (Hsu et al., 2020). 

The position of this mutation is conserved between PSEN1 and PSEN2, but multiple in silico algorithms to predict its effects 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). 

Hsu et al. first suggested the mutation could be an AD risk factor or a benign polymorphism (Hsu et al., 2018), but later classified it as probably pathogenic (Hsu et al., 2020).

Last Updated: 08 Nov 2021


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Paper Citations

  1. . Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. 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. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

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