Mutations

PSEN1 I439S

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685909 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATC to AGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was identified in a man who developed memory deficits at approximately 55 years of age and had a family history of early cognitive decline (Gómez-Tortosa et al., 2010). Two years after onset, the man showed deficits in executive functions, praxis, and verbal memory. He also had apathy and depression, as well as moderate levels of anxiety and irritability. The same mutation was found in an affected second-cousin with onset of dementia in his 50s. In addition, four affected women in previous generations died between 58 and 70 years of age after approximately a decade of cognitive deterioration.

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

Neuropathology
The neuropathology associated with this mutation is unknown. MRI showed diffuse cortical atrophy in the proband.

Biological Effect
The biological effect of this mutation is unknown, but 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 (Gómez-Tortosa et al., 2010, Xiao et al., 2021).

Last Updated: 13 Sep 2021

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References

Paper Citations

  1. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  2. . 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. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.

Other mutations at this position

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