Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Position: (GRCh38/hg38):Chr14:73217161 T>C
Position: (GRCh37/hg19):Chr14:73683869 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAC to CAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was first reported in a Korean woman with AD and a family history of early onset dementia (Park et al., 2020). Her symptoms, including memory impairment, anxiety, apathy, and disinhibition, began at age 40. Her mother, two sisters, and one brother were diagnosed with early onset dementia. Her APOE genotype was APOE3/APOE3.

The mutation was subsequently identified in two additional Korean women of different families. One had AD symptoms starting at age 39, including memory impairment, acalculia, anomia, and parkinsonism (Kim et al., 2020). She also had a family history of dementia. Disease duration was four years. Her APOE genotype was APOE3/APOE4. The other carrier suffered from memory decline starting at 41 years of age followed by language, memory, and visuospatial impairments (Shim et al., 2022). The carrier's mother presented with cognitive impairment in her 30s and died in her 40s, while her father remained neurologically healthy until his death in his 80s. All three of her siblings were healthy and cognitively normal. She was homozygous for APOE3.

This variant was not found in the gnomAD database (Kim et al., 2020).

Neuropathology
Neuropathological data are unavailable, but MRI revealed severe atrophy, especially in frontotemporal areas, in one case (Park et al., 2020), but onlyl mild cortical atrophy in the other two carriers (Kim et al. 2020, Shim et al., 2022). Additionally, in both of the latter cases, FDG-PET showed bilateral hypometabolism in parietal and temporal cortices. All three cases tested positive for amyloid deposition assessed by PiB-PET or FBB-PET.

Biological Effect
The biological effect of this mutation is unknown. The site is evolutionarily conserved (GERP score = 4.54) and in silico algorithms predicted it is probably damaging (Polyphen2), not tolerable or damaging (SIFT), and has a CADD score of 26.9, suggesting it is in the top 1 percent of deleterious variants (Park et al., 2020; Kim et al, 2020, Xiao et al., 2021). In addition, the mutation was predicted to have a structural effect, altering several PSEN1 intramolecular interactions (Shim et al., 2022).

The mutation was considered a “variant of unknown significance” given that its site had not been linked to AD previously. However, in the Kim et al. study, another mutation was discovered at the site, Y389S, in a patient who also suffered from apparent early onset familial AD. In addition, Shim and colleagues noted that three reported carriers with dementia suggests the mutation is pathogenic.

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Y389H: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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: 11 Apr 2023

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References

Mutations Citations

Paper Citations

Park JE, Kim HJ, Kim YE, Jang H, Cho SH, Kim SJ, Na DL, Won HH, Ki CS, Seo SW. Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
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.
Shim KH, Kang S, An SS, Kang MJ. Identification of the Third Case of PSEN1 Tyr389His Variant in Early-Onset Alzheimer's Disease in Korea. Int J Mol Sci. 2022 Dec 19;23(24) 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 Y389H

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