Mutations

PSEN1 L226R

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659480 T>G
dbSNP ID: rs63749961
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to CGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was first reported in a case of familial early onset Alzheimer's disease in the U.S. (Coleman et al., 2004). It was subsequently found in a man from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). This carrier had AD with an age at onset of 44 years and a family history of the disease. He suffered from memory impairment, as well as from mental and behavioral changes. He had an APOE 3/4 genotype.

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

Neuropathology

In one individual, neuropathology was found to be consistent with AD, including numerous neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex (Coleman et al., 2004).

Biological Effect

Although the biological effects of this mutation is unknown, its location was noted as consistent with the helical alignment of pathogenic mutations in transmembrane domain 5 (Coleman et al., 2004).

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: 23 Aug 2021

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References

Paper Citations

  1. . A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.
  2. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  3. . 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

Papers

  1. . Gene mutations in a Han Chinese Alzheimer's disease cohort. Brain Behav. 2019 Jan;9(1):e01180. Epub 2018 Dec 14 PubMed.

Protein Diagram

Primary Papers

  1. . A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.

Other mutations at this position

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