Mutations

PSEN1 L282P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:Chr14:73664814 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to CCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Korean woman with AD and a family history of the disease (Kim et al., 2020). Her symptoms, starting at age 40, included memory impairment, visuospatial dysfunction, abulia, apathy, and depression. Moreover, shortly prior to death and three years after disease onset, the patient developed myoclonus and seizures. Her 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 severe, bilateral hypometabolism in parietal and temporal cortices.

Biological Effect
The biological effect of this mutation is unknown, but the site is evolutionarily conserved (GERP score = 5.70) and three other mutations tied to AD have been identified at this site. In silico algorithms predicted it is probably damaging (Polyphen2), and not tolerated (SIFT). Moreover, it has a CADD score of 28.5, suggesting it is in the top 1 percent of deleterious variants. The authors classified this mutation as likely pathogenic.

Last Updated: 06 Mar 2020

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References

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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