Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685864 T>C
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was found in a Turkish man with early onset AD whose short-term memory and visuospatial skills began deteriorating at age 47 (Guven et al., 2019). An uncle of the proband had been diagnosed with AD and died at approximately 40 years of age, and the proband’s father had minor memory impairment at age 45, when he died of colon cancer. The only family member available for genetic screening was the proband’s 74-year-old mother who was cognitively healthy and did not carry the mutation. The mutation was absent from several variant databases, including the Exome Variant Server, 1000 Genome, dbSNP, and the Genome Aggregation Database.

Neuropathological data are unavailable, but reduced Aβ42 CSF levels and brain imaging data from the proband were consistent with AD. An MRI scan revealed prominent medial temporal lobe atrophy and global cortical atrophy. In addition, 18-FDG PET showed hypometabolism in parietal areas, the precuneus, and the posterior cingulate cortex.

Biological Effect
The biological effect of this mutant is unknown, but the L424 site is evolutionarily conserved and several other mutations at this site have been linked to dementia. Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Guven et al., 2019, Xiao et al., 2021). Moreover, a 3D in silico analysis predicted a shortening of the α-helices in the eighth and ninth transmembrane domains of PSEN1, and the creation of a small, additional α-helix in the linker region between the two transmembrane domains.


Alzheimer's Disease : Likely Pathogenic

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


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.


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.


Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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: 01 Dec 2022


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Paper Citations

  1. . A patient with early-onset Alzheimer's disease with a novel PSEN1 p.Leu424Pro mutation. Neurobiol Aging. 2019 Jun 13; 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A patient with early-onset Alzheimer's disease with a novel PSEN1 p.Leu424Pro mutation. Neurobiol Aging. 2019 Jun 13; PubMed.

Other mutations at this position

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