Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
Position: Chr14:73664813 C>G
dbSNP ID: rs63749937
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8


This mutation was first identified in a Belgian family affected by early onset Alzheimer’s disease (Dermaut et al., 2001). The family, known as “GB”, included five affected individuals over three generations, in a pattern suggestive of autosomal-dominant transmission. The mean age of onset in the GB family was 44.3 ± 3.1 years, with mean age at death of 53.5 ± 3.3 years.

One of the two confirmed mutation carriers in this family developed symptoms at the age of 45. In addition to cognitive deficits, he developed extrapyramidal features including a shuffling gait, sporadic myoclonus in the hands, and rigidity in the upper limbs. A few years later, he developed epileptic seizure-like episodes and generalized rigidity and myoclonus. He died at age 54. His parents had died with dementia, his mother at age 54 and his father at 83 (thought to be sporadic AD).

A cousin of the proband described above was also a mutation carrier. She developed signs of cognitive impairment at age 41. She had depression and aphasia, which progressed to complete muteness. She died at the age of 49. Her father was similarly affected by AD. He developed symptoms around age 53 and died at age 57 with neuropathologically confirmed AD. Both confirmed mutation carriers in this family had APOE genotypes of 3/4.

In addition, the variant was reported in a Chinese family with six affected family members, spanning three generations (Jia et al., 2020). Two of the affected members were diagnosed with AD and were found to be carriers of the mutation. Moreover, two healthy non-carriers were identified who were 46 and 48 years old, slightly older than the ages of onset of the two carriers, 44 and 45. The two variant carriers had APOE3/3 genotypes, as well as one of the non-carriers, while the other non-carrier had an APOE3/4 genotype.

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


Neuropathology findings are available for one confirmed mutation carrier (Dermaut et al., 2001). Overall, neuropathology was consistent with the diagnosis of AD. Neurofibrillary tangles were seen in the entorhinal cortex, the CA1 and CA2 regions of the hippocampus, and in the neocortex. Amyloid deposits were present both as dense-cored plaques and diffuse plaques in all regions analyzed. Activated microglia and astrocytes were associated with dense-cored plaques. The brain was notable for severe and extensive cerebral amyloid angiopathy (CAA) in all regions analyzed, including the neocortex, hippocampus, and cerebellum. Like the cored plaque amyloid pathology, the CAA deposits were associated with dystrophic neurites and inflammatory gliosis. There was severe white-matter loss in the neocortex. The cerebellum had notable amyloid pathology associated with severe CAA and loss of Purkinje cells.

A brain biopsy specimen of the above’s affected father also revealed plaques and tangles consistent with the diagnosis of AD. Severe CAA was also found in his brain.

Notably, the prominent CAA pathology found in the GB family did not appear to lead to strokes or stroke-like episodes.

Biological Effect

Initially findings in HEK-293 cell lines stably expressing mutant PSEN1 showed a twofold increase in the Aβ42/Aβ40 ratio compared with cells expressing wildtype PSEN1 (Dermaut et al., 2001). Consistent with this, a study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. Increased levels of Aβ43 were also observed.

In contrast, in an in vitro assay using purified proteins, the levels of Aβ40 and Aβ42 produced by the mutant were similar to those generated by wild-type PSEN1, as was the corresponding Aβ42/Aβ40 ratio (Sun et al., 2017). However, this assay may be limited in its ability to reproduce physiological processing of APP (Liu et al., 2021).

Interestingly, a study of the PSEN inhibitor MRK-560 which inhibits the activity of PSEN1, but not PSEN2, identified L282 as one of two amino acids responsible for MRK-560's isoform-dependent sensitivity (Guo et al., 2022).

The mutation has also been implicated in impairing the trafficking of the APOE receptor apoER2 (Wang et al., 2018).

Although one study reported that several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021), another study reported only one algorithm of five (PolyPhen2, PANTHER, Mutpred2, PROVEAN, Mutation Taster) predicted a damaging effect (Jia et al., 2020). In the latter study, the authors calculated a PHRED-CADD score of 24.4.


Alzheimer's Disease : Pathogenic

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


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. L282V: Mixed experimental results, but most data indicate a damaging effect.


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.


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: 18 May 2023


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News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. . Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. Brain. 2001 Dec;124(Pt 12):2383-92. PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  4. . 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.
  5. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  6. . Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. PubMed.
  7. . Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2. Neurobiol Aging. 2017 Jan;49:145-153. Epub 2016 Oct 11 PubMed.
  8. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Protein Diagram

Primary Papers

  1. . Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. Brain. 2001 Dec;124(Pt 12):2383-92. PubMed.

Other mutations at this position


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