Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640350 A>T
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was found the same year in two independent Chinese studies (Qiu et al., 2019Gao et al., 2019). One study reported a  family with 11 members affected by early onset AD, spanning three generations (Qiu et al., 2019). The proband began experiencing memory problems at 45 years of age, and her cognition progressively declined over the next two years, with additional symptoms including visuospatial impairment and irritability. By the age of 50, she was nearly bedridden. Three affected family members had similar clinical features with ages of onset ranging from 51 to 56 years.

The mutation was reported to co-segregate with disease, being present in five affected family members, but not in the proband’s only unaffected sibling. It was also absent from 100 cognitively healthy controls and 100 late-onset AD patients. The mutation was not found in three population databases (ExAC, Exome Variant Server, 1000 Genome). The family had no mutations in either the PSEN2 or APP genes. Four of the five affected members carried an APOE4 allele.

The mutation was also identified in a screen of 148 Chinese individuals diagnosed with familial Alzheimer’s disease (Gao et al., 2019). The search focused on the APP, PSEN1, and PSEN2 genes, including exons 3-12 of PSEN1. Similar to the proband in the other study, the proband in this study, a 45-year-old woman, began experiencing symptoms at age 43. Symptoms included memory loss, executive dysfunction, disorientation, and impaired visuospatial skills. She was homozygous for the APOE3 allele.


Neuropathology data are unavailable, but MRI in two individuals revealed bilateral atrophy in the hippocampus and cerebral cortex (Qiu et al., 2019).

Biological Effect

In HEK293-APPswe cells expressing PSEN1 M139L, Aβ40 levels were moderately decreased and the Aβ42/Aβ40 ratio was increased approximately 1.6-fold compared with cells expressing wild-type PSEN1 (Qiu et al., 2019). No changes in tau phosphorylation were detected.

M139 is evolutionarily conserved (Gao et al., 2019) and, although predictions from some in silico algorithms yielded conflicting results (Gao et al., 2019Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue 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).



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. M139L: Although this variant increased the Aβ42/Aβ40 ratio in a cell assay, its effect was modest.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M139L: 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. M139L: At least one family with >=3 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 PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer's Disease Increases Aβ42/Aβ40 ratio. J Alzheimers Dis. 2019;69(1):199-212. PubMed.
  2. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
  3. . 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.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

External Citations

  1. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A Novel PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer's Disease Increases Aβ42/Aβ40 ratio. J Alzheimers Dis. 2019;69(1):199-212. PubMed.
  2. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.

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