Mutations

PSEN1 A431V

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219177 C>T
Position: (GRCh37/hg19):Chr14:73685885 C>T
dbSNP ID: rs63750083
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCA to GTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a Japanese man with a family history of early onset dementia affecting six members, spanning three generations (Matsushita et al., 2002). The mutation was absent from the proband’s unaffected mother and from 200 healthy controls and 120 patients with sporadic AD, as well as from the gnomAD variant database (gnomAD v2.1.1, August 2021).. The proband presented with mild cognitive impairment at age 47 and was diagnosed with AD 16 months later.

Neuropathology
Although neuropathological data are unavailable, FDG-PET imaging of the proband’s brain a month after the initial MCI diagnosis, revealed hypometabolism in the posterior cingulate gyrus, posterior and lateral parietal cortices, and medial temporal regions. One day after the MCI diagnosis, the proband’s levels of Aβ42 in the CSF were within the normal range, but tau and phospho-tau levels were elevated.

Biological effect
The biological effect of this mutation is unknown, but a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that A431 is apposed to the β-strand of APP which forms part of a hybrid, three-stranded β–sheet required for cleavage (Zhou et al., 2019; Jan 2019 news). Moreover, 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*

*Note that a single affected carrier has been reported for this variant.

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

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. A431V: Cryo-EM data suggest residue is of functional importance.

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.

PP1-P

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.

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: 22 Feb 2022

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Matsushita S, Arai H, Okamura N, Ohmori T, Takasugi K, Matsui T, Maruyama M, Iwatsubo T, Higuchi S. Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer's disease. Biol Psychiatry. 2002 Nov 1;52(9):907-10. PubMed.
  2. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. 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. Matsushita S, Arai H, Okamura N, Ohmori T, Takasugi K, Matsui T, Maruyama M, Iwatsubo T, Higuchi S. Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer's disease. Biol Psychiatry. 2002 Nov 1;52(9):907-10. PubMed.

Other mutations at this position

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