Mutations

PSEN1 L262F

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198047 G>C
Position: (GRCh37/hg19):Chr14:73664755 G>C
dbSNP ID: rs63750248
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a fibroblast line from the NIA Aging Cell Repository derived from an individual diagnosed with AD (Forsell et al., 1997). Age at onset was 56 years and symptoms included disorientation, aphasia, and memory loss. Two other fibroblast lines derived from affected siblings also carried the mutation. These individuals suffered from dementia onset at 47 and 48 years of age. One of them, diagnosed with AD based on a brain biopsy, experienced short-term memory loss and decreased word-finding ability. The other sibling presented with inappropriate jocularity and occasional paraphrasias. Samples from unaffected individuals in the same family were unavailable.

This variant was also identified in a screen of 148 Chinese individuals diagnosed with familial Alzheimer’s disease (Gao et al., 2019). The search focused on the APP, PSEN1, and PSEN2 genes, including exons 3-12 of PSEN1. The proband was a 40-year-old man whose symptoms started at age 35 and included memory impairment, executive dysfunction, disorientation, dyscalculia, and disrupted visuospatial skills. Dysarthria and extrapyramidal signs were also reported. His APOE genotype was E3/E3. Including the proband, four family members, spanning three generations, were affected.

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

Neuropathology
A brain biopsy in one case revealed neuropathology consistent with AD (Forsell et al., 1997).

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed L262F generates less Aβ40 and more Aβ42 than the wildtype protein, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017).

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). 

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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.

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: 22 Feb 2022

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References

Paper Citations

  1. Forsell C, Froelich S, Axelman K, Vestling M, Cowburn RF, Lilius L, Johnston JA, Engvall B, Johansson K, Dahlkild A, Ingelson M, St George-Hyslop PH, Lannfelt L. A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease. Neurosci Lett. 1997 Sep 26;234(1):3-6. PubMed.
  2. Gao Y, Ren RJ, Zhong ZL, Dammer E, Zhao QH, Shan S, Zhou Z, Li X, Zhang YQ, Cui HL, Hu YB, Chen SD, Chen JJ, Guo QH, Wang G. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
  3. 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.
  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

No Available Further Reading

Protein Diagram

Primary Papers

  1. Forsell C, Froelich S, Axelman K, Vestling M, Cowburn RF, Lilius L, Johnston JA, Engvall B, Johansson K, Dahlkild A, Ingelson M, St George-Hyslop PH, Lannfelt L. A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease. Neurosci Lett. 1997 Sep 26;234(1):3-6. PubMed.

Other mutations at this position

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Alzpedia

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