Mutations

PSEN1 L424F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
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

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.

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)..

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 01 Dec 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

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. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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.

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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