Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217162 A>C
Position: (GRCh37/hg19):Chr14:73683870 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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 several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this substitution is damaging (Kim et al., 2020, Xiao et al., 2021). 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. Of note, in the same study, another mutation was discovered at the site, Y389H, in a patient who also suffered from apparent early onset familial AD.

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

Mutations Citations

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 Y389S

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