Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637692 G>C
dbSNP ID: rs63751141
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGC to TCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This mutation was first reported in two Italian families, both of whom had a history of familial dementia. Affected members of both families met NINCDS-ADRDA criteria for probable AD; however, the clinical presentation in one family included atypical features.

The three affected members of the family known as FLO57 are described as having a fairly typical presentation of early onset AD, and began to exhibit memory decline in their early 50s, with a mean age of onset of approximately 53.5 years. In contrast, depression, social isolation, and sporadic mutism were the first symptoms of the proband in the other family, known as “FLO28.” These symptoms, which began at age 49, were followed by memory decline and extrapyramidal signs, with rigidity and bradykinesia. Hallucinations and delusions followed, and the proband became progressively more mute and parkinsonian. The proband’s mother had dementia with aggressive behavior, but symptoms reportedly began considerably later, at age 70. No mutations in MAPT were detected in the proband of FLO28, suggesting that PSEN1 C92S may produce a variable clinical phenotype, presenting as either fairly typical early onset AD or with an atypical presentation characterized by extrapyramidal signs and early psychiatric features (Tedde et al., 2003).



Biological Effect

In transfected cultured cells, as well as in patient fibroblasts, this mutation has been reported to increase Aβ42 secretion (Lewis et al., 2000Zhang et al., 2000; Assini et al., 2003). In the patient cells, Aβ40 secretion was unchanged and, consequently, the Aβ42/Aβ40 ratio was increased. An in vitro assay using purified proteins to test the ability of the mutant to cleave the APP-C99 substrate, however, revealed a drastic reduction in both Aβ42 and Aβ40 production, with Aβ40 levels being undetectable (Sun et al., 2017). Although in C. elegans the mutant also interfered with Notch processing (Zhang et al., 2000), it did not affect Notch cleavage in human cells (Okochi et al., 2000). 

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: 30 Jul 2021


No Available Comments

Make a Comment

To make a comment you must login or register.


Paper Citations

  1. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  2. . The presenilin 1 C92S mutation increases abeta 42 production. Biochem Biophys Res Commun. 2000 Oct 14;277(1):261-3. PubMed.
  3. . Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased A beta42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans. Neuroreport. 2000 Sep 28;11(14):3227-30. PubMed.
  4. . Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology. 2003 Jan 14;60(1):150. PubMed.
  5. . 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.
  6. . A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells. J Biol Chem. 2000 Dec 29;275(52):40925-32. 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.

Further Reading


  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002; 23(Suppl 1):S312.

Protein Diagram

Primary Papers

  1. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.


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.