Mutations

PSEN1 P267A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664768 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in an African-American man with Alzheimer’s disease who had a strong family history of dementia (Ringman et al., 2016). He developed memory problems at age 62 and died at age 69. His identical twin brother was diagnosed with AD at the age of 59 and their mother developed dementia in her mid-60s. The mutation was also identified in another African-American man, thought to be unrelated. He developed symptoms at age 45 and met clinical criteria for AD at age 51. The report notes a strong family history of dementia in this man as well, with evidence of autosomal dominant transmission, but further details were not reported.

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

Neuropathology

Neuropathology is available for one mutation carrier and showed frequent neuritic plaques, including in the neocortex (Braak stage VI), and severe cerebral amyloid angiopathy. Lewy bodies were not present.

Biological Effect

The biological effect of this variant is unknown, but a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue appears to help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news). Moreover, 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). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Last Updated: 24 Sep 2021

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References

News Citations

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

Paper Citations

  1. . Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol. 2016 Mar;75(3):284-90. Epub 2016 Feb 17 PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 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.
  4. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol. 2016 Mar;75(3):284-90. Epub 2016 Feb 17 PubMed.

Other mutations at this position

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