Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Atypical Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Atypical Dementia
Position: (GRCh38/hg38):Chr14:73219155 C>G
Position: (GRCh37/hg19):Chr14:73685863 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation has been reported in two individuals with several differences in clinical presentation. It was first documented in a young Spanish woman suffering from an early onset dementia syndrome with a complex clinical phenotype. At the age of 26 she developed symptoms of anorexia nervosa, followed by memory and attention deficits by age 30. Four years later she had developed changes in personality and behavior, including impulsivity and aggression. Her condition deteriorated, and she developed aphasia, stereotyped behaviors, myoclonus, and seizures. Possible diagnoses of Huntington's disease and sporadic Creutzfeldt-Jakob disease were considered and excluded. Her symptoms were indicative of frontal dysfunction reminiscent of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). No family members were affected by early onset dementia, although her maternal grandfather developed dementia after age 80. Segregation of the mutation with disease could not be assessed, but it was absent in 178 unrelated individuals (Robles et al., 2009).

A subsequent report described the mutation in a Bulgarian man diagnosed with early onset familial AD (Stoychev et al., 2019). His initial symptoms, surfacing at approximately 38 years of age, included rapid and marked impairment of episodic memory and speech, in addition to slow reactivity and irritability. Aphasic symptoms and episodes of disorientation developed subsequently. Cognitive decline with further deterioration of speech, apraxia, acalculia, and ataxia occurred over the following two years, as well as the emergence of parkinsonian symptoms, bradykinesia and tremor. Unlike the Spanish patient, this individual did not develop myoclonus nor seizures. Of note, the patient also suffered from lupus erythematosus with predominant skin manifestations. The patient's father developed dementia with an approximate age at onset of 44 years.

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

Neuropathology

Unknown. CT and SPECT imaging of the Spanish woman's brain showed diffuse cortical and subcortical atrophy as well as hypoperfusion affecting the frontal, temporal, and parietal lobes. Fronto-temporal cortical atrophy was the dominant feature of the Bulgarian case, as revealed by CT and MRI scans.

Biological Effect

Compared with wild-type PSEN1, this mutation increased both Aβ40 and Aβ42 production, and doubled the Aβ42/Aβ40 ratio as assessed by in vitro assays using isolated proteins (Bai et al., 2015; Sun et al., 2017).

Although several in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because only one carrier with AD has been reported—cosegregation data are lacking—and the variant is absent, or very rare, in the gnomAD database.

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.

PM5-M

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

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: 01 Dec 2022

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References

Paper Citations

Robles A, Sobrido MJ, García-Murias M, Prieto JM, Lema M, Santos D, Paramo M. Clinical picture of a patient with a novel PSEN1 mutation (L424V). Am J Alzheimers Dis Other Demen. 2009 Feb-Mar;24(1):40-5. PubMed.
Stoychev KR, Stoimenova-Popova M, Chumpalova P, Ilieva L, Swamad M, Kamburova-Martinova Z. A Clinical Case of Patient Carrying Rare Pathological PSEN1 Gene Mutation (L424V) Demonstrates the Phenotypic Heterogenity of Early Onset Familial AD. Front Psychiatry. 2019;10:857. Epub 2019 Dec 11 PubMed.
Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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 L424V

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