Mutations

PSEN1 Y159F

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640411 A>T
dbSNP ID: rs778630379
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in a woman whose family included four members, spanning three generations, affected by early onset dementia (Kerchner and Holbrook, 2012). At 43 years of age, the proband presented with short-term memory loss that began six months earlier. A neuropsychological assessment revealed severe impairments in episodic memory, visuoconstructional ability, language, and executive function. She also had mild depression, but no changes in personality, behavior, or motor skills. The proband’s mother and a maternal uncle developed dementia in their early 50s, and her maternal grandmother showed signs of dementia at 68. The mutation was detected in both the proband and her affected uncle. The proband was homozygous for the APOE3 allele and had no mutations in APP, PSEN2, or other regions of the PSEN1 gene.

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

Neuropathology

Neuropathological data are unavailable, but levels of AD biomarkers in the cerebrospinal fluid of the proband, including Aβ42, total tau, and 181-phosphorylated tau, were suggestive of an AD diagnosis. A brain MRI scan failed to reveal any abnormalities.

Biological Effect

The biological effect of the mutation is unknown, but it is in a region that is evolutionarily conserved between mouse and human. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that Y159 appears to help stabilize the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019).

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 : 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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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. Y159F: 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. Y159F: Variant Y159S was classified as pathogenic.

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: 15 Apr 2022

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References

News Citations

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

Paper Citations

  1. . Novel presenilin-1 Y159F sequence variant associated with early-onset Alzheimer's disease. Neurosci Lett. 2012 Dec 7;531(2):142-4. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . 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. . Novel presenilin-1 Y159F sequence variant associated with early-onset Alzheimer's disease. Neurosci Lett. 2012 Dec 7;531(2):142-4. PubMed.

Other mutations at this position

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