Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637732 T>G
dbSNP ID: rs63750321
Coding/Non-Coding: Coding
Mutation Type: Point, 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 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 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, including numerous neurofibrillary tangles and senile plaques in the hippocampus with scattered plaques in the cortex (Finckh et al., 2000).

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). 

Last Updated: 27 Aug 2021


No Available Comments

Make a Comment

To make a comment you must login or register.


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. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . 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 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  4. . 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


Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.