Mutations

PSEN1 A231T

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659494 G>A
dbSNP ID: rs63749836
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCC to ACC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was found in a French individual with familial early onset Alzheimer's disease. The family included four affected individuals with ages of onset ranging from 45 to 57 years (Campion et al., 1995). It was also reported in a French sporadic case of AD with onset at age 50 and disease duration of 3 years (Lanoiselée et al., 2017).

The mutation was absent from 50 unrelated controls, as well as from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Neuropathology data are unavailable, but the patient with sporadic AD had elevated tau and phospho-tau levels in cerebrospinal fluid (Lanoiselée et al., 2017). Of note, CSF Aβ42 levels were within the normal range in this individual.

Biological Effect

This variant disrupted APP processing, but the pathogenicity of the disruption is uncertain. An in vitro assay using purified proteins to test its ability to cleave the APP-C99 substrate revealed decreased Aβ40 and Aβ42 production, and an increased Aβ42/Aβ40 ratio (Sun et al., 2017). A subsequent study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 did not detect a substantial change in the Aβ42/Aβ40 ratio, but showed a decrease in the Aβ37/Aβ42 ratio, a robust indicator of reduced Aβ trimming activity that correlated with pathogenicity (Liu et al., 2022; Apr 2022 news). This cell-based study also revealed reduced levels of all Aβ peptides (Aβ37, Aβ38, Aβ39, Aβ40, Aβ42, Aβ43).

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 (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely 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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. A231T: This variant decreased production of short and long Aβ peptides. It decreased the Aβ37/Aβ42 ratio; results for Aβ42/Aβ40 were mixed.

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.

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: 17 Nov 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. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  2. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  3. . 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.
  4. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  5. . 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

Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Protein Diagram

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

Other mutations at this position

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