Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198114 G>T
Position: (GRCh37/hg19):Chr14:73664822 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to TCT
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 54, included memory impairment, acalculia, delusion, depression, and anxiety. Disease duration was five years. 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 bilateral hippocampal atrophy, and FDG-PET showed bilateral hypometabolism in the temporal cortex. In addition, she tested amyloid-positive as assessed by PiB-PET.

Biological Effect
The biological effect of this mutation is unknown, but the site is evolutionarily conserved (GERP score = 5.82). 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). Kim and colleagues reported predictions of probably damaging (Polyphen 2) and tolerable (SIFT), and a CADD score of 25.9 (Kim et al., 2020).

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.

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: 22 Feb 2022

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References

Paper Citations

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.
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.

Mutations

PSEN1 A285S

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