Pathogenicity: Alzheimer's Disease : Likely Benign
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73678599 G>A
dbSNP ID: rs199715992
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10


This variant was identified in a French study that screened 129 individuals with sporadic AD diagnosed according to the National Institute of Aging–Alzheimer’s Association criteria with an age at onset below 51 (Lanoiselée et al., 2017). The mutation carrier had progressive cognitive decline beginning at age 45, and a disease duration of four years. The carrier was homozygous for the APOE3 allele. It is unknown if the mutation arose de novo, as parental DNA was unavailable.

The variant was found in the gnomAD variant database at a frequency of 0.00003183 with an allele count of nine (gnomAD v2.1.1, Sep 2021). In a subset of the gnomAD database that excludes data from neurological studies, the frequency was similar, 0.00003925, with the same allele count (gnomAD v2.1.1 (non-neuro), Sep 2021).

Neuropathological data are unavailable. Cerebrospinal fluid biomarkers for AD were measured in the mutation carrier, however. Although levels of Aβ42 were reduced consistent with AD (487 pg/ml), tau and phospho-tau were in the normal range (217 pg/ml; and 35 pg/ml, respectively).

Biological Effect
The biological effect of this mutation is unknown. In silico algorithms to predict its effects (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021) and the CADD-PHRED tool, which integrates diverse information, gave it a low deleteriousness score below 20 (CADD v.1.6, Sep 2021). Based on the criteria developed by Guerreiro and colleagues (Guerreiro et al., 2010), this mutation was classified as possibly pathogenic (Lanoiselée et al., 2017) and of uncertain significance based on the ACMG/AMP guidelines (Xiao et al., 2021).

Last Updated: 07 Oct 2021


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Paper Citations

  1. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  2. . 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.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  4. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1
  2. gnomAD v2.1.1 (non-neuro)
  3. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.

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