Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685864 T>C
Coding/Non-Coding: Coding
Mutation Type: Point, 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.

Last Updated: 04 Aug 2021


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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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