Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73685864 T>G
dbSNP ID: rs63751032
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was first described in a Polish family (Pedigree J.P) affected by early onset dementia with prominent motor impairment (Kowalska et al., 1999). The reported pedigree showed at least six affected individuals over four generations (Kowalska et al., 2004). Onset in this family was very early, ranging from 30 to 35 years of age, and deterioration was rapid, with death occurring four to five years after onset. The proband developed progressive memory and language impairment at age 30. Within a year he had also developed sporadic myoclonic jerks and left-side hemiparesis.

This mutation was also reported in a Polish Caucasian woman who at the age of 34 developed behavioral and personality changes, including apathy and aggression, as well as cognitive decline. She exhibited increasingly severe involuntary movements, including choreic movements in the upper and lower extremities. She also developed gait problems and seizures. She had a family history of early onset dementia accompanied by involuntary movements. Her father had died at age 37 following personality changes, memory problems, and motor disturbances. Her paternal aunt died at age 40 with similar symptoms. The proband's paternal grandfather had died in his 40s with a diagnosis of "psychiatric disease." Segregation of the mutation with disease could not be assessed due to lack of DNA from family members. Huntington's disease was excluded by genetic testing, and no pathogenic mutations were observed in APP, PSEN2, or PRNP  (Klimkowicz-Mrowiec et al., 2014).

The mutation was also found in a 38-year-old Dutch man who presented with dementia, spastic paraparesis, and impairments in frontal executive function, mimicking familial Creutzfeld Jakob disease and frontotemporal dementia (de Bot et al., 2009).  However, the patient had CSF biomarkers characteristic of AD: increased total- and phosphorylated-tau levels, and decreased Aβ42.

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


Neuropathological data are unavailable, but MRI showed cortical and subcortical atrophy with a thin corpus callosum (Klimkowicz-Mrowiec et al., 2014).

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. This variant also increased Aβ43 levels by approximately fivefold compared with wildtype PSEN1.

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).


Alzheimer's Disease : Pathogenic*

*Carriers of this variant had heterogenous phenotypes.

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


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


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. L424R: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.


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.


Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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: 01 Dec 2022


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News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. . A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization. Folia Neuropathol. 1999;37(1):57-61. PubMed.
  2. . Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  3. . Clinical Presentation of Early-Onset Alzheimer's Disease as a Result of Mutation in Exon 12 of the PSEN-1 Gene. Am J Alzheimers Dis Other Demen. 2014 Dec;29(8):732-4. Epub 2014 Jun 6 PubMed.
  4. . CSF studies facilitate DNA diagnosis in familial Alzheimer's disease due to a presenilin-1 mutation. J Alzheimers Dis. 2009;17(1):53-7. PubMed.
  5. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  6. . 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


  1. . Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.
  2. . Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.
  3. . Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. PubMed.

Protein Diagram

Primary Papers

  1. . A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization. Folia Neuropathol. 1999;37(1):57-61. PubMed.

Other mutations at this position


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