Pathogenicity: Frontotemporal Dementia : Not Classified
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr14:73683938 G>A
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTA to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11


This variant was found in four members, spanning two generations, of a family in Southern Italy with autosomal dominant, early onset frontotemporal dementia (Bernardi et al., 2009). Three of the affected individuals, who were siblings, developed similar symptoms, fulfilling the clinical criteria for FTD. The fourth, their mother, had already died at the time of the study, but clinical records suggest she had a similar phenotype.

Although the mutation was absent from 100 previously screened familial AD patients and from 100 cognitively healthy controls (Bernardi et al., 2009), it is found in the gnomAD variant database. In the (non-neuro) subdivision of gnomAD, which excludes data from neurological studies, its allele count is three and frequency 0.00001320 (gnomAD (non-neuro) v2.1.1, Aug 2021). 


Although neuropathological data are unavailable, in one case, 18FDG-PET showed hypometabolism in the parietal and frontal cortices, as well as in the putamen and caudate. In another case, SPECT showed widespread cortical hypoperfusion.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a severe decrease in Aβ42 production and undetectable levels of Aβ40 (Sun et al., 2017). In silico algorithms to predict the effects of this variant 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). Moreover, Koriath and colleagues predicted the variant’s penetrance to be less than 10 percent, and described it as "most likely benign" or causing an "only small increase in risk" (Koriath et al., 2018)

Last Updated: 13 Sep 2021


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Paper Citations

  1. . Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging. 2009 Nov;30(11):1825-33. PubMed.
  2. . 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.
  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.
  4. . 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.

External Citations

  1. gnomAD (non-neuro) v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging. 2009 Nov;30(11):1825-33. PubMed.


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