Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659452 G>C
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was first identified in a woman with a strong family history of early onset AD (Norton et al., 2009). The family included eight affected members, spanning four generations, with a mean age at onset of 45.5 years and a mean age at death of 55.5 years. In addition to the proband, a first-degree cousin was also found to carry the mutation. The clinical progression of the disease of the cousin's son was reported. At age 44, he had anxiety attacks and depression, and by 46, memory loss and disorientation prevented him from doing his delivery job. At age 51, he developed incontinence and confusion, and went through several hospitalizations for agitation and aggressive behavior. He died at age 52.

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

At autopsy, the brain of the patient who was clinically followed, revealed neuropathology typical of AD with mild generalized atrophy. In addition, a large number of cotton-wool plaques was observed.

Biological Effect
In HEK293 cells transiently cotransfected with a human APP cDNA and a PSEN1 cDNA construct carrying the G217R mutation, the secreted Aβ42/Aβ40 ratio was elevated approximately three-fold compared with that of control cells expressing a wild-type PSEN1 construct. An in vitro assay using purified proteins to test the mutant’s ability to cleave the APP-C99 substrate revealed a more modest increase in the Aβ42/Aβ40 ratio and a drop in production of both Aβ40 and Aβ42 peptides (Sun et al., 2017).

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).

Last Updated: 04 Aug 2021


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Paper Citations

  1. . Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool plaques. Neurology. 2009 Aug 11;73(6):480-2. PubMed.
  2. . 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.
  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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool plaques. Neurology. 2009 Aug 11;73(6):480-2. PubMed.

Other mutations at this position


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