PSEN1 D40del (delGAC)


Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS4, PM2, PM4
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr14:73170827_73170829 GAC>---
Position: (GRCh37/hg19):Chr14:73637535_73637537 GAC>---
dbSNP ID: rs759538127
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: 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.

The variant was also reported in a study that screened the APP, PSEN1, and PSEN2 genes in 1,431 AD patients from the Belgian neurology consortium BELNEU (Perrone et al., 2020). Two carriers were identified, both homozygous for the APOE3 allele. The CSF of one of them was analyzed and found to have decreased levels of Aβ42 and Aβ43, with normal levels of Aβ40, consistent with AD. This individual also had increased levels of sAPPα and sAPPβ.

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, Sep 2021).

Of note, a French individual with a synonymous mutation, D40del (delACG), developed AD at age 52 (Nicolas et al., 2015).


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

Three different studies yielded conflicting results. Mouse neuroblastoma cells transfected with PSEN1 D40del secreted more Aβ42 and similar amounts of Aβ40 compared with cells expressing wild-type PSEN1 (Hsu et al., 2020). However, similar experiments using human embryonic kidneys cells indicated both the Aβ42/Aβ40 and the Aβ37/Aβ42 ratios were similar to those of control cells  (Liu et al., 2022, Apr 2022). Of note, the latter study showed that both ratios were useful for distinguishing control versus AD samples, but Aβ37/Aβ42 outperformed Aβ42/Aβ40. Moreover, an in vitro assay using purified proteins to test the ability of the mutant to cleave the APP-C99 substrate revealed a robust decrease in Aβ42 production, and undetectable levels of Aβ40 (Sun et al. 2017). The nucleotide deletion of the mutant in this latter study was not specified.

D40 is conserved between PSEN1 and PSEN2, but the deletion was not predicted to be pathogenic in silico by Protein Variation Effect Analyzer (PROVEAN) (Nygaard et al., 2014). A study applying several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021)

Hsu classified this variant as a risk factor (Hsu et al., 2020) and Perrone and colleagues suggested it could be considered "likely pathogenic" based on the earlier in vitro observations and their findings of altered Aβ peptides in CSF, particularly Aβ43 (Perrone et al., 2020). 


Alzheimer's Disease : Uncertain Significance*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. D40del (delGAC): The variant was reported in 3 or more unrelated patients with AD, and absent from controls.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. D40del (delGAC): Single amino acid deletion.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 23 Mar 2022


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Mutations Citations

  1. PSEN1 D40del (delACG)

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

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. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  3. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  4. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  5. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  6. . 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.
  7. . 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. . 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.

Other mutations at this position


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