Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659507 T>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to CGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This presenilin-1 mutation was detected in a Spanish woman diagnosed with early onset Alzheimer’s disease. She first developed episodic memory impairment at the age of 47, along with reduced language fluency and word-finding difficulties. Behavioral changes, notably apathy and self-neglect, also appeared early. Gait disturbance, pyramidal signs, and myoclonus were absent. The reported pedigree indicates eight individuals over two generations affected by early onset dementia in a pattern consistent with autosomal-dominant inheritance, although a lack of samples precluded segregation analysis. Clinical information was limited for affected family members, but the mean age of onset was reported as 45 years (range: 41 to 60 years) and the disease course was noted to be rapid. PSEN2 and APP were not screened (Antonell et al., 2011).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).


Unknown. MRI showed bilateral atrophy, especially within the parietal and temporal lobes. Analysis of the cerebral spinal fluid showed low levels of Aβ42 and elevated total tau and phospho-tau 181 (Antonell et al., 2011).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it abrogates Aβ40 production and drastically reduces Aβ42 production (Sun et al., 2017). Also, the mutation caused incomplete endoproteolytic processing of PSEN1. In silico, PolyPhen predicts that the L235R mutation is possibly damaging. It is classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Antonell et al., 2011).

Last Updated: 16 Jul 2021


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Paper Citations

  1. . A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease. Neurosci Lett. 2011 May 27;496(1):40-2. 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. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease. Neurosci Lett. 2011 May 27;496(1):40-2. PubMed.

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