Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659569 T>A
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to AAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in a Chinese family including five members spanning two generations affected by early onset dementia (Li et al., 2019). The proband presented with short-term memory impairment at 40 years of age. At 41, she was diagnosed with early onset AD and showed progressive mental decline, including disorientation, confusion, and impaired cognitive function. In addition, at age 42, she developed static tremor, kinetic tremor, hypermyotonia, impaired speech, and generalized tonic-clonic seizures. Three of the proband’s siblings and her mother suffered from severe memory impairment in their late 30s or early 40s.

Two mutations were found in the proband’s PSEN1 gene: Y256N and V255V, a synonymous mutation. The former was also identified in two of the proband’s affected siblings, but not in her unaffected father, nor in an unaffected sibling. The mutation was also absent from 200 Chinese healthy controls and two genetic variant databases (ExAC and 1000 Genomes).

Although neuropathological data are unavailable, a brain MRI of the proband revealed bilateral temporal lobe and hippocampal atrophy.

Biological Effect
The biological effect of this variant is unknown, but several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, MutPred2, SNAP, and Reve) predicted this variant is damaging (Li et al., 2019Xiao et al., 2021). 

Last Updated: 24 Aug 2021


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Paper Citations

  1. . Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. 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. . Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. PubMed.

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