Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
DIAN-TU Eligibility: Yes
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198047 G>T
Position: (GRCh37/hg19):Chr14:73664755 G>T
dbSNP ID: rs63750248
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant was identified in a screen of 148 Chinese individuals diagnosed with familial Alzheimer’s disease (Gao et al., 2019). The search focused on the APP, PSEN1, and PSEN2 genes, including exons 3-12 of PSEN1. The proband was a 40-year-old man whose symptoms started at age 35 and included memory impairment, executive dysfunction, disorientation, dyscalculia, and disrupted visuospatial skills. Dysarthria and extrapyramidal signs were also reported. His APOE genotype was E3/E3. Including the proband, four family members, spanning three generations, were affected.

A subsequent paper reported an average age at onset of 53.3 years (std error 2.7) in a group of carriers from Sweden and China (Liu et al., 2025).

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, Mar 2024).

Neuropathology
Neuropathological data are unavailable.

Biological Effect
An in vitro assay using purified proteins to test the ability of the mutant protein (nucleotide change unspecified) to cleave the APP-C99 substrate revealed L262F generates less Aβ40 and more Aβ42 than the wildtype protein, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). This variant’s PHRED-scaled CADD score was 22, above the commonly used threshold of 20 to assess deleteriousness (CADD v1.7, Mar 2025).

The Dominantly Inherited Alzheimer Network Trials Unit classified this variant as likely pathogenic (Liu et al., 2025).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic*

*Carriers of L262F variants are eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for Alzheimer’s disease (Liu et al., 2025).

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

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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: 26 Mar 2025

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References

Paper Citations

Gao Y, Ren RJ, Zhong ZL, Dammer E, Zhao QH, Shan S, Zhou Z, Li X, Zhang YQ, Cui HL, Hu YB, Chen SD, Chen JJ, Guo QH, Wang G. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
Liu H, Marsh TW, Shi X, Renton AE, Bowling KM, Ziegemeier E, Wang G, Cao Y, Aristel A, Li J, Dickson A, Perrin RJ, Goate AM, Fernández V, Day GS, Doering M, Daniels A, Gordon BA, Benzinger TL, Hassenstab J, Ibanez L, Supnet-Bell C, Xiong C, Allegri R, Berman SB, Fox NC, Ryan N, Huey ED, Vöglein J, Noble JM, Roh JH, Jucker M, Laske C, Ikeuchi T, Sanchez-Valle R, Schofield PR, Chrem Mendez P, Chhatwal JP, Farlow M, Lee JH, Levey AI, Levin J, Lopera F, Martins R, Niimi Y, Rosa-Neto P, Morris JC, Bateman RJ, Karch CM, Cruchaga C, McDade E, Llibre-Guerra JJ. The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset. Brain. 2025 Feb 4; Epub 2025 Feb 4 PubMed.

Mutations

PSEN1 L262F (G>T)

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