Mutations

PSEN1 M233I (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659502 G>C
dbSNP ID: rs63751479
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was detected in a patient with neuropathologically confirmed Alzheimer's disease. At age 28, the patient began to experience memory problems that affected activities of daily living. Her disease progressed quickly, with worsening memory and language impairments and stereotyped and perseverative behavior. By age 31, pyramidal signs were present, associated with a cerebellar syndrome, rigidity, and myoclonic jerking. She continued to deteriorate, becoming immobile, incontinent, and mute, with swallowing difficulties and generalized tonic-clonic seizures. She died at age 36.

The parents of the proband were unaffected and did not carry the mutation. Paternity was confirmed by microsatellite typing, therefore the mutation is thought to have arisen de novo in the proband. The mutation was absent in 50 unrelated control subjects (Portet et al., 2003). To note, the mutation was erroneously reported as M233L.

Neuropathology

A right frontal brain biopsy showed pathology consistent with a diagnosis of AD, including amyloid plaques and tau-positive neurofibrillary tangles. Astrocytic gliosis, spongiosis, and prion disease were not observed.

Biological Effect

Although the biological effect of this specific mutant has not been examined, the M233I (G>A) mutation was classified as definitely pathogenic (Wallon et al., 2012) according to the algorithm proposed by Guerreiro et al., 2010. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Although some in silico algorithms to predict the effects of this variant 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.

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

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. M233I (G>C): 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.

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: 22 Feb 2022

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

  1. PSEN1 M233I (G>A)

News Citations

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

Paper Citations

  1. . Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu). Neurology. 2003 Oct 28;61(8):1136-7. PubMed.
  2. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 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. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu). Neurology. 2003 Oct 28;61(8):1136-7. PubMed.

Other mutations at this position

Alzpedia

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.