Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM5, PP2, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh37/hg19):Chr14:73637706 G>A
Position: (GRCh38/hg38):Chr14:73170998 G>A
dbSNP ID: rs63750852
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant was identified in France in individual(s) who developed Alzheimer’s disease (AD) (Liu et al., 2025). However, detailed information on the carrier(s) is unavailable. The variant was classified as “Pathogenic” and 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. Data used to determine DIAN-TU eligibility include family history suggesting an autosomal dominant pattern of inheritance, documentation of amnestic-predominant, progressive cognitive impairment leading to AD dementia (preferably with AD biomarkers and/or neuropathological confirmation of AD in at least one family member), low frequency of the variant in a large population database such as the gnomAD, evidence of co-segregation with disease within a family, and assessment of Aβ42 and Aβ40 levels in a cell-based assay. Additional supportive criteria include conservation of the affected amino acid between PSEN1 and PSEN2, presence of other AD pathogenic variants at the same amino acid site, and in silico prediction of damaging effects.

This variant was found at a frequency of 0.0000081 in the gnomAD variant database (gnomAD v4.1.1, March 2025). Carriers included 13 heterozygotes, 12 of whom were of European ancestry.

Neuropathology
Neuropathological data are unavailable.

Biological Effect
In a cell-based assay, this variant increased the Aβ42/Aβ40 ratio compared to wildtype PSEN1, but decreased production of both Aβ40 and Aβ42 (Marsh et al., 2025). Consistent with these findings, the variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (31) suggesting a damaging effect (CADD v.1.7, March 2025).

Pathogenicity

Alzheimer's Disease : Not Classified*

*Carriers of this variant 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). Alzforum has not yet classified this variant because carrier data are not yet published. 

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

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References

Paper Citations

1. 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.
2. Marsh JA, Huang G, Bowling K, Renton AE, Ziegemeier E, Ball T, Pottier C, Cruchaga C, Day GS, Bateman RJ, Llibre-Guerra JJ, McDade E, Karch CM. Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics. 2025 Jan 27;:e00527. Epub 2025 Jan 27 PubMed.

Further Reading

No Available Further Reading