Mutations

PSEN1 L219R

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659459 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was detected in a Japanese woman with early onset Alzheimer's disease. Cognitive impairment started at age 51 and she met NINCDS-ADRDA clinical criteria for Alzheimer's disease (Ikeda et al., 2013). Symptoms included memory loss, apathy, depression, and apraxia of daily behaviors. In addition, emotional and social disturbances were reported. At age 57, the patient also developed difficulty walking. APOE genotyping revealed she carried APOE3 and APOE4 alleles.The patient's mother and elder sister also suffered from dementia in their 50s. 

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

Neuropathology

Neuropathology data are unavailable, but brain imaging revealed atrophy and reduced blood flow in temporal, parietal, and frontal lobes. Also, widespread microbleeds were found in brain, brainstem, and cerebellum. Levels of phospho-tau in CSF were elevated, while those of Aβ42 were reduced.

Biological Effect

Unknown, but 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).

Last Updated: 10 Sep 2021

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References

Paper Citations

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.
  2. . 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

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.

Other mutations at this position

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