Mutations

PSEN1 I168T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653583 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATA to ACA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This variant was found in an exome sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls who did not have evidence of neuropathology at the time of their deaths. The mutation carrier was a Caucasian man who was diagnosed with AD at the age of 86. His APOE genotype was ε2/ε4. He died at age 94 with extensive neuropathology (Braak stage V). He had no known family history of dementia (Sassi et al., 2014).

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

The individual carrying this variant was found to have severe neuropathology consistent with AD (Braak V) (Sassi et al., 2014).

Biological Effect

In an in vitro assay with isolated proteins, this mutant produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Sassi et al., 2014, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). It has been classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014).

Last Updated: 21 Sep 2021

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References

Paper Citations

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 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.
  4. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.

Other mutations at this position

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