PSEN1 D40del (delACG)


Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM4, BS1
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637533-73637535 ACG>---
dbSNP ID: rs759538127
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: ACG 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 this deletion is the absence of one amino acid (D) from the presenilin-1 protein sequence. The reading frame remains intact. This deletion was detected by whole-exome sequencing in one of 424 French people with early onset AD. This individual had apparently sporadic AD with onset at age 52. APOE genotype was E3/E4 (Nicolas et al., 2015). The frequency of this variant in the gnomAD database was 0.0001344 with an allele count of 38 (gnomAD v2.1.1, Sep 2021). Its penetrance was estimated at 2 percent or less (Koriath et al., 2018). 

Of note, a synonymous deletion, D40del (delGAC), has also been identified in AD patients.


Neuropathology data are unavailable, but a D40del (delGAC) carrier had decreased CSF levels of Aβ42 and Aβ43, with normal levels of Aβ40 (Perrone et al., 2020).

Biological Effect

Experiments in vitro indicate the deletion of D40 alters Aβ peptide production resulting in an increase in the Aβ42/Aβ40 ratio. Mouse neuroblastoma cells transfected with PSEN1 D40del (delGAC) secreted more Aβ42 and similar amounts of Aβ40 compared with cells expressing wild-type PSEN1 (Hsu et al., 2020). However, 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 applyling additional 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). Based on the allele count (39) and the frequency of this variant in the gnomAD database, the variant was described as "most likely benign" or causing an "only small increase in risk" (Koriath et al., 2018).


Alzheimer's Disease : Uncertain Significance*

*Note that a single affected carrier has been reported for this variant.

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


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. D40del (delACG): Two assays showed an increase in the Aβ42/Aβ40 ratio, but results were inconsistent regarding the production levels of each peptide.


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


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

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

Last Updated: 22 Feb 2022


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Mutations Citations

  1. PSEN1 D40del (delGAC)

Paper Citations

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; 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. . 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.
  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. . 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.
  6. . 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.
  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. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.

Other mutations at this position


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