Mutations

PSEN1 A409T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217221 G>A
Position: (GRCh37/hg19):Chr14:73683929 G>A
dbSNP ID: rs63750227
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to ACC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was found in a 58-year-old AD patient without a family history of AD. The mutation was absent from a sample of 100 non-demented individuals 60 to 85 years old (Aldudo et al., 1999) and from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology 

Unknown.

Biological Effect

Although an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate suggested a lack of a damaging effect, a cell-based assay indicated otherwise. In vitro, the mutant decreased Aβ40 and Aβ42 production and decreased the Aβ42/Aβ40 ratio (Sun et al., 2017). However, in cells, production of the toxic peptide Aβ43 and the Aβ42/Aβ40 ratio were increased, while Aβ38 and Aβ40 levels were decreased (Kakuda et al., 2021). (Although Aβ42 production was decreased, its reduction was less than that of Aβ40). A switch in the stepwise processing pathway that leads to Aβ43 production may contribute to the cell-based results and, interestingly, analysis of multiple PSEN1 AD-associated mutants revealed that increased Aβ43 levels and increased production by the alternate pathway correlated with younger ages at disease onset.

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 : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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. A409T: Functional observations were mixed, but cell-based assays monitoring a wide range of Aβ peptide lengths suggest a damaging effect. 

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: 04 Mar 2022

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References

Paper Citations

  1. Aldudo J, Bullido MJ, Valdivieso F. DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433-9. PubMed.
  2. Sun L, Zhou R, Yang G, Shi Y. 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. Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  4. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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. Aldudo J, Bullido MJ, Valdivieso F. DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433-9. PubMed.

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