PSEN1 G378fs


Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683837_73683838 ->G
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Frame Shift
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11


This mutation, identified in a Moroccan woman, involves the insertion of one nucleotide (G) resulting in a frameshift at codon 378. The mutation carrier presented with symptoms of progressive memory impairment at age 63. Her symptoms, including decreased autonomy and aphasia, were typical of AD. The reported pedigree shows five affected individuals over two generations. Segregation with disease could not be assessed due to lack of DNA from other family members (El Kadmiri et al., 2014).

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


Unknown. MRI of the proband showed hippocampal and parahippocampal atrophy (El Kadmiri et al., 2014).

Biological Effect

An assessment of secreted Aβ40 and Aβ42 in mouse neuroblastoma N2A cells expressing the PSEN1 G378fs mutation on a PSEN1/PSEN2 null background also revealed an increased Aβ42/Aβ40 ratio, with a decrease in both Aβ40 and Aβ42 levels (Hsu et al., 2020). Position 378 is conserved between PSEN1 and PSEN2 and several in silico algorithms predicted it is damaging (Xiao et al., 2021). Hsu et al. classified it as probably pathogenic (Hsu et al., 2020).


Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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. G378fs: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. G378fs: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


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.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

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


  1. I must admit to being somewhat skeptical about the results presented in this paper and in a sister paper on novel mutations in APP. It seems remarkable (and highly improbable) that the researchers would discover numerous novel frameshift familial AD (FAD) mutations truncating the open reading frames of PSEN1 and PSEN2 among a small number of families when the only such mutation that I know of previously published is K115Efx10 in PSEN2 (Jayadev et al., 2010) among the 180-plus FAD mutations known in these two genes (the rest of which preserve the genes' open reading frames). The sequence data presented is not especially convincing.


    . Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.

    View all comments by Michael Lardelli
  2. We have concerns about the validity of the frameshift mutations in PSEN1 and PSEN2 reported here. Beyond the fact that there is no genetic evidence in the literature that PSEN1 or PSEN2 haploinsufficiency causes Alzheimer’s disease, we are not convinced by the DNA sequencing electropherogram images in Figures 1 and 2. From a technical point of view, a weak signal and/or background noise may lead to the false detection of single base pair insertions or deletions. Hence, the existence of the mutations in these patients appears to be uncertain. Likewise, we have similar concerns about a related paper reporting frameshift mutations in APP (El Kadmiri et al., 2014).


    . Novel mutations in the amyloid precursor protein gene within Moroccan patients with Alzheimer's disease. J Mol Neurosci. 2014 Jun;53(2):189-95. Epub 2014 Mar 14 PubMed.

    View all comments by Anne Rovelet-Lecrux

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Paper Citations

  1. . Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease. Neuroscience. 2014 Jun 6;269:215-22. Epub 2014 Apr 4 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease. Neuroscience. 2014 Jun 6;269:215-22. Epub 2014 Apr 4 PubMed.

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