PSEN1 D40del (delGAC)


Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73637535 GAC>---
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: GAC to ---
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4


This variant is a trinucleotide deletion within exon 4 of PSEN1. The consequence of the deletion is the absence of one amino acid (D) from the presenilin-1 protein sequence. The reading frame remains intact. The deletion was detected in one individual with atypical Alzheimer's disease who presented with clinical features of the behavioral variant of frontotemporal dementia (bvFTD) (Nygaard et al., 2014). The patient began to notice symptoms at age 48, including mild psychomotor impairment and personality changes. These symptoms were followed by severe impairment in executive function and later by an amnestic syndrome. He was initially diagnosed with FTLD of the bvFTD type, but the pattern of memory problems combined with the fibrillary Aβ deposits in the brain suggested AD. The patient did not have a family history of dementia. Genetic analysis of family members was not possible. The patient did not carry any known mutations in APP or PSEN2.

In a subsequent study, the D40 deletion was described as "most likely benign" or causing an "only small increase in risk" based on its allele count (39) and frequency (0.0138 percent) in the gnomAD variant database (Koriath et al., 2018). The penetrance was calculated to be two percent or less.


Unknown. MRI showed progressive cortical atrophy involving the lateral frontal lobes most prominently (Nygaard et al., 2014). Medial temporal lobe structures were also affected. Imaging by PET with florbetapir showed fibrillary Aβ deposits particularly in the frontal lobes.

Biological Effect

An in vitro assay using purified proteins to test the ability of PSEN1 with a D40 deletion to cleave the APP-C99 substrate revealed a robust decrease in Aβ42 production, and undetectable levels of Aβ40 (Sun et al. 2017). However, the deletion does not cause a frame shift and is not predicted to be pathogenic in silico by Protein Variation Effect Analyzer (PROVEAN) (Nygaard et al., 2014).

Last Updated: 16 Jul 2019


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Paper Citations

  1. . A Novel Presenilin 1 Mutation in Early-Onset Alzheimer's Disease With Prominent Frontal Features. Am J Alzheimers Dis Other Demen. 2014 Jan 24;29(5):433-435. PubMed.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A Novel Presenilin 1 Mutation in Early-Onset Alzheimer's Disease With Prominent Frontal Features. Am J Alzheimers Dis Other Demen. 2014 Jan 24;29(5):433-435. PubMed.

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