Mutations

PSEN1 Y389S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683870 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAC to TCC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was identified in a Korean man with probable AD and a family history of the disease (Kim et al., 2020). His symptoms, starting at age 50, included memory impairment, visuospatial dysfunction, aphasia, acalculia, apraxia, simultagnosia, apathy, abulia, and parkinsonism. Disease duration was three years. His APOE genotype was APOE3/APOE3.

This variant was not found in the gnomAD database, nor in 500 Korean controls.

Neuropathology
Neuropathological data are unavailable, but MRI revealed mild, diffuse cortical atrophy, and FDG-PET showed bilateral hypometabolism in the parieto-temporal cortex. In addition, he tested amyloid positive as assessed by PiB-PET.

Biological Effect
The biological effect of this mutation is unknown. The site is evolutionarily conserved (GERP score = 4.53) and in silico algorithms predicted it is probably damaging (Polyphen2), and not tolerable (SIFT). Moreover, it has a CADD score of 26.8, suggesting it is in the top 1 percent of deleterious variants. The mutation was considered a “variant of unknown significance” given that its site had not been linked to AD previously. However, in the same study, another mutation was discovered at the site, Y389H, in a patient who also suffered from apparent early onset familial AD.

Last Updated: 06 Mar 2020

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References

Mutations Citations

  1. PSEN1 Y389H

Paper Citations

  1. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.

Other mutations at this position

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