Mutations

PSEN1 L424F

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Dementia, Depression
Reference Assembly: GRCh37/hg19
Position: Chr14:73685863 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in two members of a Bulgarian family with seven individuals affected by dementia spanning three generations (Mehrabian et al., 2006). One of the mutation carriers was diagnosed with depression at 54 years of age and went on to develop dementia and grand mal epilepsy. The other presented with memory loss, aggression, delusions, and hallucinations at age 60, followed by development of dementia. The additional five affected members also suffered from behavioral abnormalities and dementia.

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

Neuropathology
Neuropathology data are unavailable. The authors report that neuroimaging in both patients revealed severe brain atrophy with white-matter changes (Mehrabian et al., 2006).

Biological Effect
The biological effect of this variant is unknown. Although some in silico algorithms to predict its effects on protein function yielded conflicting results (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)..

Last Updated: 22 Sep 2021

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References

Paper Citations

  1. . Novel PSEN1 gene mutation in a large Bulgarian pedigree with Alzheimer's disease and atypical phenotype. Eur J Neurol. 2006;13(Suppl 2):41.
  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
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel PSEN1 gene mutation in a large Bulgarian pedigree with Alzheimer's disease and atypical phenotype. Eur J Neurol. 2006;13(Suppl 2):41.

Other mutations at this position

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