Mutations

PSEN1 I238_K239insI

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659518_73659519 --->TAA
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Insertion
Codon Change: --- to TAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation, involving the insertion of three nucleotides (TAA), was identified in a young man with cognitive decline initially attributed to Korsakoff syndrome due to a history of chronic alcohol dependency (Roeber et al., 2015). It is unclear at what age his symptoms started, but by age 35 his executive functioning was severely impaired. In addition, he exhibited a variety of motor symptoms including dysphagia, myoclonus, gait problems, and spastic tetraparesis. He also developed seizures. His disease was apparently sporadic.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Cerebral MRI showed generalized cortical and subcortical atrophy. Postmortem examination revealed cortical atrophy, mainly of the frontal lobe. Neuropathology consistent with AD was documented (Braak and Braak stage VI, CERAD C). Specifically, numerous neurofibrillary tangles and amyloid plaques were observed, as well as ghost tangles, neuropil threads, and neuritic plaques. Cerebral amyloid angiopathy was also present.

Biological Effect

Unknown. This mutation, involving the insertion of the trinucleotide TAA, results in the insertion of one amino acid (isoleucine), but does not cause a frameshift. Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) 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. In addition, the clinical phenotype is complicated by alcoholism.

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

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. I238_K239insI: Variant located at edge of mutational hot spot.

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.

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

Paper Citations

  1. Roeber S, Müller-Sarnowski F, Kress J, Edbauer D, Kuhlmann T, Tüttelmann F, Schindler C, Winter P, Arzberger T, Müller U, Danek A, Kretzschmar HA. Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.
  2. 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. Roeber S, Müller-Sarnowski F, Kress J, Edbauer D, Kuhlmann T, Tüttelmann F, Schindler C, Winter P, Arzberger T, Müller U, Danek A, Kretzschmar HA. Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.

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.