Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
Position: Chr14:73664826 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 8


This mutation was found in a Spanish family with seven affected members, spanning three generations, with a mean age of disease onset of 40 years (Sánchez-Valle et al., 2007). The proband developed cognitive impairment, with predominant memory loss, at age 35. Over the years, disruptions in language, praxis, and visuospatial functions developed, as well as behavioral and parkinsonian symptoms. The proband was diagnosed with probable AD, subsequently confirmed at autopsy. Cognitive decline in all affected family members—four of five of the proband’s siblings, one of her parents, a sibling of her parent, and one of her five children—was characterized by early memory loss. Three of these members also suffered from brain hematoma. The mutation was identified in the proband and her affected child, but was absent from her healthy sibling.

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


Neuropathological examination of the proband’s brain revealed an abundance of cotton–wool plaques throughout the neocortex and hippocampal formation (Sánchez-Valle et al., 2007). Severe amyloid angiopathy affecting meningocortical vessels was also reported. Degenerating neurons with hyperphosphorylated tau were seen in entorhinal, limbic, and neocortical areas, as well as in the amygdala, basal ganglia, and thalamus. Neuropathological observations of an affected sibling also revealed cotton-wool plaques, as well as a large lobar hematoma associated with severe amyloid angiopathy.

In mutation carriers from this family, CSF Aβ42 levels correlated with time to disease onset in asymptomatic individuals, reaching a minimum when symptoms appeared (Fortea et al., 2011). In contrast, total tau levels in CSF became elevated in symptomatic individuals and correlated with clinical severity.

Biological Effect
Several studies indicate this mutation impairs γ-secretase function. A mass spectrometry analysis of multiple Aβ isoforms in the CSF of six mutation carriers, for example, revealed lower levels of Aβ37, Aβ38, Aβ39, and Aβ42 than non-carriers (Portelius et al., 2012). In contrast, Aβ15 and Aβ20 were increased. Moreover, in HEK293 cells transfected with Swedish mutant βAPP and the PSEN1 L286P mutant, levels of Aβ42 and Aβ43 were increased compared with those of cells expressing mutant βAPP and wild-type PSEN1 (Kulik et al., 2000). In addition, production rates of Aβ38 and Aβ40 were found to be decreased in isolated brain membranes from a patient (Szaruga et al., 2015).  The mutation appears to impair the fourth γ-secretase cleavage in at least one of the carboxypeptidase-like Aβ production lines that sequentially digest Aβ into shorter peptides as revealed by a decrease in the Aβ38/Aβ42 (product/substrate) ratio.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, L286 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

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).


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.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L286P: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


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. L286P: At least one family with 2 affected carriers and >=1 unaffected noncarriers.


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: 22 Feb 2022


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas. Eur J Neurol. 2007 Dec;14(12):1409-12. PubMed.
  2. . Cerebrospinal fluid biomarkers in Alzheimer's disease families with PSEN1 mutations. Neurodegener Dis. 2011;8(4):202-7. PubMed.
  3. . The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease. Mol Med Report. 2012 Apr;5(4):1111-5. PubMed.
  4. . Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5913-8. PubMed.
  5. . Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  7. . 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


  1. . Cerebrospinal fluid biomarkers in Alzheimer's disease families with PSEN1 mutations. Neurodegener Dis. 2011;8(4):202-7. PubMed.
  2. . Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. J Alzheimers Dis. 2010;22(3):909-22. PubMed.

Protein Diagram

Primary Papers

  1. . A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas. Eur J Neurol. 2007 Dec;14(12):1409-12. PubMed.

Other mutations at this position


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