Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637732 T>G
dbSNP ID: rs63750321
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This mutation was found in a patient from Germany identified as patient 2 (Finckh et al., 2000). The patient experienced symptom onset at age 52 and was diagnosed with probable Alzheimer’s disease (AD) at age 59 with an MMSE score of 13 out of 30. At age 60 she developed Parkinson-like symptoms and died with severe dementia at age 63. Autopsy excluded Parkinson’s disease and confirmed the diagnosis of AD. Family history included early onset dementia in the patient’s mother (onset approximately age 50) and maternal grandmother (onset <60 years), but segregation analysis was not possible.

The variant was also identified in four members of a family suffering from early onset AD, a father and three children (Maarouf et al., 2008; Yang et al., 2022). Two daughters began experiencing symptoms at ages 60 and 56, and died after 8 and 11 years, respectively. The former had an APOE2/3 genotype.

In addition, the variant was reported in a Chinese family with four affected members, spanning four generations (Jia et al., 2020). The proband was diagnosed with AD, with symptoms emerging at 63 years, and the mean age at onset in the family was 64 years. Two affected members, including the proband, were found to carry the mutation. The proband's APOE genotype was E3/E3.  

A single allele was reported in the gnomAD variant database, corresponding to a frequency of 0.000003977 (gnomAD v2.1.1, Aug 2021). It was absent from the gnomAD "non-neuro" database which contains only samples from individuals who were not ascertained for having a neurological condition in a neurological case/control study (gnomAD v2.1.1, May 2021).


Neuropathology consistent with AD was seen at autopsy in the German patient, including numerous neurofibrillary tangles and senile plaques in the hippocampus with scattered plaques in the cortex (Finckh et al., 2000). Severe AD neuropathology was also found in brain tissues from the two sisters, characterized by diffuse Aβ plaques and angiopathy (Maarouf et al., 2008; Yang et al., 2022). Quantification of Aβ levels in the cerebral cortex of one sister revealed an Aβ42/Aβ40 ratio close to 1 (Maarouf et al., 2008). Moreover, cryo-electron microscopy images of Aβ42 fibrils in brain tissue from the other sister revealed a core of paired S-shaped protofilaments (Yang et al., 2022; Jan 2022 news). These filaments were arranged in a pattern distinct from that seen in sporadic AD, but similar to the pattern observed in the brain of another individual with familial AD (carrying the APP V717F Indiana mutation). Type II filaments were also found in related disorders and in APP knock-in mice.

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. This mutant also reduced total secreted Aβ levels.

Jia and colleagues reported that four of the five in silico algorithms they applied predicted a damaging effect, and the PHREDD CADD tool, which integrates diverse information, gave it a high deleteriousness score of 27 (Jia et al., 2020). Another study using SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database reported the algorithms yielded conflicting results (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.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. F105L: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


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.


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. Cryo-EM Unveils Distinct Aβ42 Fibril Structures for Sporadic, Familial AD

Mutations Citations

  1. APP V717F (Indiana)

Paper Citations

  1. . High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
  2. . Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008 Nov 20;3:20. PubMed.
  3. . Cryo-EM structures of amyloid-β 42 filaments from human brains. Science. 2022 Jan 14;375(6577):167-172. Epub 2022 Jan 13 PubMed.
  4. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. 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. . 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
  2. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.

Other mutations at this position


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