Mutations

PSEN1 P355S

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PM1, PP2, BS1, BP4
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr14:73211876 C>T
Position: (GRCh37/hg19):Chr14:73678584 C>T
dbSNP ID: rs376433615
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCT to TCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was found in a 60-year-old woman from Italy who suffered from dementia with pseudo-psychotic symptoms similar to those associated with frontotemporal dementia (Monacelli et al., 2019). The authors described the condition as a frontal variant form of AD. None of the patient’s known family members had developed similar symptoms; only her mother had dementia, but it was late-onset. The patient presented with abulia, apathy, loss of initiative, poor self-care, social withdrawal, and hyporexia. In addition, she had delusions, blunted emotions, and obsessive thinking. Cognitive impairment initially included short-term memory loss, temporal disorientation, and impaired visuospatial organization, and later involved language and executive functions. She also developed limb rigidity and postural instability.

The variant was also identified in a Belgian AD patient who also carried a mutation in the APP gene: G625_S628del (Perrone et al., 2021).

In the gnomAD database, the frequency of the P355S variant was 0.00005304 with 15 alleles, 12 from individuals of African ancestry (gnomAd v2.1.1, July 2021) and in the non-neuro subset of gnomAD, which excludes data from neurological studies, the frequency was 0.00004796 with 11 alleles, 9 from individuals of African ancestry (gnomAD v2.1.1 (non-neuro), July 2021).

Neuropathology
Neuropathology data are unavailable, but a brain MRI scan revealed microbleeds in the cortex, basal ganglia, and subcortical white matter suggestive of amyloid angiopathy. FDG-PET showed bilateral frontotemporal hypometabolism. The authors suspected Lewy body pathology.

Biological Effect
The biological effect of this mutation is unknown, but the authors hypothesize it perturbs the catalytic activity of PSEN1 by disrupting hybrid β-sheet formation between PSEN1 and its APP substrate (Perrone et al., 2021). The hypothesis is based on a cryo-electron microscopy study which revealed the atomic structure of human γ-secretase in complex with a transmembrane APP fragment (Zhou et al., 2019). However, in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021) and the CADD-PHRED tool, which integrates diverse information, gave it a low deleteriousness score, below 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Likely Benign

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. P355S: Cryo-EM data suggest residue is of functional importance.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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

Paper Citations

  1. Monacelli F, Martella L, Parodi MN, Odetti P, Fanelli F, Tabaton M. Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation. J Alzheimers Dis. 2019;70(1):11-15. PubMed.
  2. Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R, BELNEU Consortium. Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. 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.
  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
  2. gnomAD v2.1.1 (non-neuro)
  3. CADD v.1.6,

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Monacelli F, Martella L, Parodi MN, Odetti P, Fanelli F, Tabaton M. Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation. J Alzheimers Dis. 2019;70(1):11-15. PubMed.

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