Mutations

PSEN1 A434V

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Posterior Cortical Atrophy
Position: (GRCh38/hg38):Chr14:73219186 C>T
Position: (GRCh37/hg19):Chr14:73685894 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GTT
Genomic Region: Exon 12

Findings

This variant was identified in a 52-year-old Italian female with a progressive visuospatial disorder and apraxia, and mild amnestic and attentional deficit (Roveta et al. 2023).  A diagnosis of Alzheimer’s disease (AD) with posterior cortical atrophy (PCA) was made based on neuropsychological assessment via the Mini-Mental State Examination (MMSE) & the Montreal Cognitive Assessment (MoCA), neuroradiological imaging, and AD biomarker examination via biochemical assays.

As the patient had a family history of presenile dementia, next-generation sequencing was used to analyze the coding exons of a panel of 25 dementia-associated genes. The analysis revealed she was a carrier of PSEN1 A434V with an APOE3/E4 genotype. The variant was absent from two public genetic databases, gnomAD (v.2.1.1 and v.4.0.0, Feb 2024) and TOPMed BRAVO (freeze 8). 

Neuropathology
Currently, postmortem neuropathological data are not available from the variant carrier, but neuroradiological evaluation showed posterior cortical atrophy and hypometabolism in the occipital, parietal, and temporal cortex via computed tomography of the brain (CT), magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET).  In addition, ELISA assays on core AD biomarkers showed a reduction of Aβ42 and the Aβ42/Aβ40 ratio, and increased total tau in cerebrospinal fluid, while a PET scan confirmed the presence of cerebral amyloidosis in the brain (Roveta et al. 2023).

Biological Effect
Although the biological effect of this variant is unknown, A434 has been shown to directly interact with APP, forming part of the PAL (P433-A434-L435) motif implicated in the recognition of APP by γ-secretase (Sato et al., 2008; Zhou et al., 2019; Jan 2019 news). Moreover, evolutionary analysis has indicated A434 is a highly conserved nucleotide and the missense substitution A434V was predicted to be deleterious by several algorithms (Roveta et al. 2023; PHRED-scaled CADD score 28.7, v 1.7, Feb 2024). Also of note, two other variants at this position, A434T and A434C, have been classified as pathogenic.

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.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. A434V: Variant is in a mutational hot spot and 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.

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: 21 Feb 2024

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

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

Mutations Citations

  1. PSEN1 A434T
  2. PSEN1 A434C

Paper Citations

  1. Roveta F, Marcinnò A, Grassini A, Ferrandes F, Cermelli A, Boschi S, Gallone S, Atzori C, Imperiale D, Dentelli P, Pasini B, Brusco A, Rubino E, Rainero I. A Novel PSEN1 Variant Leading to Posterior Cortical Atrophy: A Case Report. J Alzheimers Dis Rep. 2023;7(1):469-473. Epub 2023 May 31 PubMed.
  2. Sato C, Takagi S, Tomita T, Iwatsubo T. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci. 2008 Jun 11;28(24):6264-71. PubMed.
  3. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Roveta F, Marcinnò A, Grassini A, Ferrandes F, Cermelli A, Boschi S, Gallone S, Atzori C, Imperiale D, Dentelli P, Pasini B, Brusco A, Rubino E, Rainero I. A Novel PSEN1 Variant Leading to Posterior Cortical Atrophy: A Case Report. J Alzheimers Dis Rep. 2023;7(1):469-473. Epub 2023 May 31 PubMed.

Other mutations at this position

View Table

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.