Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
DIAN-TU Eligibility: Yes
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198042 G>C
Position: (GRCh37/hg19):Chr14:73664750 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTT to CTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Spanish woman who developed cognitive impairment, including memory loss, as well as gait disruption secondary to spastic paraparesis, at age 40 (Jiménez-Caballero et al., 2008; Gómez-Tortosa et al., 2010). Her brother and mother developed similar symptoms in their late 40s. In a subsequent paper, the mean age at onset of a group of affected carriers in Spain was reported as 40.3 (std error 0.3) years (Liu et al., 2025). Whether these affected carriers were related to the original proband is unknown.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathological data are not available, but MRI of the proband’s brain showed symmetrical cortical and subcortical atrophy, particularly in the frontal lobes, and SPECT revealed bilateral temporal hypoperfusion.

Biological Effects
The biological effects of this variant are unknown, but 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). 

This variant has been classified as likely pathogenic (Xiao et al., 2021; Liu et al., 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). This variant was not classified by Alzforum because of insufficient data: it is uncertain if the reported carriers are related, and functional and co-segregation data are lacking.

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. Jiménez Caballero PE, Lladó A, de Diego Boguna C, Martin Correa E, Serviá Candela M, Marsal Alonso C. A novel presenilin 1 mutation (V261L) associated with presenile Alzheimer's disease and spastic paraparesis. Eur J Neurol. 2008 Sep;15(9):991-4. PubMed.
2. Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Muñoz DG, Jiménez-Huete A, Rábano A, Sainz MJ, Guerrero R, Gobernado I, Pérez-Pérez J, Jiménez-Escrig A. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
3. 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.
4. 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.

External Citations

1. gnomAD v2.1.1

Further Reading