Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73683845 C>G
dbSNP ID: rs63750687
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11


This mutation was identified in the proband of a Bulgarian family with three members affected by Alzheimer's disease. The clinical course in this family was characterized by early onset, rapid progression, and some atypical features, such as extrapyramidal signs and spastic paraparesis. The proband developed symptoms at age 32 and died at age 37 (Mehrabian et al., 2004; Dintchov Traykov et al., 2009).

A Japanese family with the L381V mutation has also been described. The family, referred to as P3000, included a father and daughter with probable AD according to NINCDS-ADRDA criteria. The father died in his early 40s with severe dementia and progressive gait impairment. The daughter presented first with apathy at age 29, followed by progressive memory deficits and gait disturbance. Two years later she had also developed spastic paraparesis (Ikeuchi et al., 2008).

In addition, a Chinese woman whose memory began deteriorating at age 29 also carried this mutation (Chen et al., 2022). She developed rigidity, cerebellar ataxia, and spastic paraparesis. Of note, the parents of this patient did not carry the mutation, indicating the mutation arose de novo.

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


Although neuropathological data are unavailable, in one carrier, PET scans revealed amyloid accumulation in bilateral frontal, parietal, and temporal cortices, as well as in the posterior cingulate and cerebellum, and tau pathology in both cerebral and cerebellar cortices (Chen et al., 2022). In addition, in this same patient, MRI scans were normal at age 37 but revealed whole brain atrophy by age 39. Also, reduced dopamine transporter labeling was observed bilaterally in the anterior and posterior putamen. At age 37, hypometabolism was observed bilaterally in the parietal occipital area, spreading to the posterior cingulate and temporal cortex by age 39.

Analysis of the Aβ peptides in the cerebrospinal fluid of another carrier revealed reduced Aβ38 and Aβ40 levels that were similar in magnitude suggesting proportional reductions in Aβ43 to Aβ40 production and Aβ42 to Aβ38 production, as observed for other familial AD mutations (Kakuda et al., 2021). In contrast, Aβ42 and Aβ43 levels were differentially affected, with relatively high levels of Aβ43 resulting in an elevated Aβ43/Aβ42 ratio.

Biological Effect 

When expressed in HEK293 cells, this mutation appeared to alter the specificity of the carboxypeptidase-like γ-cleavage, resulting in increased secreted Aβ42, and an increased Aβ42/Aβ40 ratio (Ikeuchi et al., 2008Li et al., 2016). Similar results were obtained in an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate (Sun et al., 2017). Moreover, a subsequent study in transfected HEK cells revealed a large increase in the production of the toxic Aβ43 peptide (Kakuda et al., 2021). To probe the underlying mechanism of this disruption, and those of other mutants, the small peptides released during APP processing were analyzed.

In addition, L381V Levels of the N-terminal fragment (NTF) of presenilin-1 was decreased, suggesting impaired endoproteolysis of the protein, and NICD levels were decreased, suggesting reduced Notch cleavage by γ-secretase (Ikeuchi et al., 2008).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated that L381 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for APP cleavage (Zhou et al., 2019; Jan 2019 news). 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

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


De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.


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. L381V: 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. L381V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


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.


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 Nov 2022


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . A novel PSEN1 mutation in an EOAD family with spastic paraparesis and extrapyramidal signs. Eur J Neurol. 2004; 11(Suppl 2):16,
  2. . Novel PSEN1 mutation in a Bulgarian patient with very early-onset Alzheimer's disease, spastic paraparesis, and extrapyramidal signs. Am J Alzheimers Dis Other Demen. 2009 Oct-Nov;24(5):404-7. PubMed.
  3. . Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
  4. . Very Early-Onset Alzheimer's Disease in the Third Decade of Life with de novo PSEN1 Mutations. J Alzheimers Dis. 2022;85(1):65-71. PubMed.
  5. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  6. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  7. . 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.
  8. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  9. . 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

Protein Diagram

Primary Papers

  1. . Novel PSEN1 mutation in a Bulgarian patient with very early-onset Alzheimer's disease, spastic paraparesis, and extrapyramidal signs. Am J Alzheimers Dis Other Demen. 2009 Oct-Nov;24(5):404-7. PubMed.
  2. . A novel PSEN1 mutation in an EOAD family with spastic paraparesis and extrapyramidal signs. Eur J Neurol. 2004; 11(Suppl 2):16,

Other mutations at this position


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