Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73659507 T>C
dbSNP ID: rs63749835
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7
Research Models: 1


This mutation was first reported in a French family, SAL 510, with familial early onset Alzheimer’s disease (Campion et al., 1996). As reported, this family had four affected individuals who met NINCDS-ADRDA criteria for probable or definite AD. The mutation segregated with disease in this family: three affected siblings were heterozygous carriers and two unaffected siblings were not carriers. Age of onset in this family ranged from 29 to 35 (mean: 32.5 years). A subsequent study that expanded on this report described five affected family members over three generations, with a revised age of onset ranging from 29-39 years (Campion et al., 1999).Symptoms included progressive memory and language impairment, tonic-clonic seizures, neurological signs (including Babinski), and myoclonus. Disease progression was rapid, with severe dementia within a few years of symptom onset. The clinical picture in this family was notable for the presence of seizures, typically starting in childhood or early adolescence. However, the authors note that the seizures did not always co-occur with dementia, and that a second genetic variant predisposing to epilepsy may be responsible. Interestingly, in another study of French individuals, seizures were reported in two of three carriers of this mutation (Zarea et al. 2016). 

The L235P mutation was also reported in another study in an individual with AD, but further clinical details, demographic information, and family history were not described (Rogaeva et al., 2001).

In addition, the L235P was found in a patient of German origin, known as P.54. The patient experienced onset of dementia at age 32. Her mother died at age 34 with an autopsy-confirmed diagnosis of AD. A great-grandparent of P.54 was of French ancestry, leading the authors to speculate a possible French founder effect for this mutation given the discovery of the mutation in the French SAL 510 family (Finckh et al., 2005).

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


Neuropathology consistent with AD in at least one affected mutation carrier. Postmortem examination showed a high density of senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Spongiosis was noted in layer 2. Tangles were observed also in the basal nucleus of Meynert, septal and raphe nuclei, and the locus coeruleus (Campion et al., 1996).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it abrogates Aβ40 production and drastically reduces Aβ42 production (Sun et al., 2017). Expression in transgenic mice, however, was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic protein (Yang et al., 2012).

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.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. L235P: Functional observations are mixed, but they consistently showed a damaging effect.


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.


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. L235P: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


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)

Research Models

This mutation has been introduced into mouse models of disease including the APP751SL/PS1 KI double mutant, which also expresses APP with the London (V717I) and Swedish (K670N/M671L) mutations.

In a single transgenic mouse model, the L235P mutation was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic proteins (Yang et al., 2012).

Last Updated: 22 Feb 2022


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Research Models Citations

  1. APP751SL/PS1 KI

Paper Citations

  1. . Increased phosphorylation of tau and synaptic protein loss in the aged transgenic mice expressing familiar Alzheimer's disease-linked presenilin 1 mutation. Neurochem Res. 2012 Jan;37(1):15-22. PubMed.
  2. . A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8;7(10):1582-4. PubMed.
  3. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  4. . Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
  5. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  6. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 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. . 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8;7(10):1582-4. PubMed.

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