Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653601 T>G
dbSNP ID: rs63751025
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to CGG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6


This mutation was found in two Bavarian sisters from a family including seven individuals affected by dementia, spanning four generations (Klünemann et al., 2004). The sisters developed early memory impairment and severe personality changes, and were initially diagnosed with frontotemporal dementia. Mean age of dementia onset in the family was 48 years, ranging between 46 and 56 years. The mutation was absent from 200 healthy controls.

Neuropathology in one case was consistent with AD, including generalized brain atrophy with the hippocampus and temporal cortex most severely affected. The distribution of amyloid plaques, neurofibrillary tangles, neuropil threads, and dystrophic neurites was consistent with AD Braak stage VI. In addition, abundant Lewy bodies were found in the amygdala and entorhinal cortex.

Biological Effect
The biological effect of this mutation is unknown. However, the mutation is a nonconservative substitution in an evolutionarily conserved position, and other AD-related mutations have been reported at this site. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in L174 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

Last Updated: 14 Aug 2019


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Novel PS1 mutation in a Bavarian kindred with familial Alzheimer disease. Alzheimer Dis Assoc Disord. 2004 Oct-Dec;18(4):256-8. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel PS1 mutation in a Bavarian kindred with familial Alzheimer disease. Alzheimer Dis Assoc Disord. 2004 Oct-Dec;18(4):256-8. PubMed.

Other mutations at this position


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