Mutations

PSEN1 L282P

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198106 T>C
Position: (GRCh37/hg19):Chr14:73664814 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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 several pathogenic variants have been identified at this site. Moreover, in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted it is damaging (Kim et al., 2020, Xiao et al., 2021). Kim and colleagues classified it as likely pathogenic.

Interestingly, a study of the PSEN inhibitor MRK-560 which inhibits the activity of PSEN1, but not PSEN2, identified L282 as one of two amino acids responsible for MRK-560's isoform-dependent sensitivity (Guo et al., 2022).

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.

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.

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.

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: 18 May 2023

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References

Paper Citations

  1. Kim YE, Cho H, Kim HJ, Na DL, Seo SW, Ki CS. PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. 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.
  3. Guo X, Wang Y, Zhou J, Jin C, Wang J, Jia B, Jing D, Yan C, Lei J, Zhou R, Shi Y. Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Kim YE, Cho H, Kim HJ, Na DL, Seo SW, Ki CS. 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

View Table

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