Mutations

PSEN1 H214N

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659443 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAC to AAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This PSEN1 mutation was found in a Caucasian woman from Italy who met clinical criteria for probable Alzheimer’s disease (Piccoli et al., 2016). Her symptoms started at age 46 with executive dysfunction. She had a family history of dementia: Her maternal grandfather developed dementia at 50 years of age and died at 55. The proband’s mother presented with memory decline at age 55, and died at 62. Segregation with disease could not be determined.

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

Neuropathology

Unknown. CT scan showed diffuse cerebral atrophy more pronounced in medial temporal lobes.

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 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Moreover, several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted it is damaging (Piccoli et al., 2016, Xiao et al., 2021).

Last Updated: 10 Sep 2021

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References

News Citations

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

Paper Citations

  1. Piccoli E, Rossi G, Rossi T, Pelliccioni G, D'Amato I, Tagliavini F, Di Fede G. Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer's disease identified by targeted exome sequencing. Neurobiol Aging. 2016 Apr;40:192.e7-11. Epub 2016 Feb 28 PubMed.
  2. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. 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. Piccoli E, Rossi G, Rossi T, Pelliccioni G, D'Amato I, Tagliavini F, Di Fede G. Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer's disease identified by targeted exome sequencing. Neurobiol Aging. 2016 Apr;40:192.e7-11. Epub 2016 Feb 28 PubMed.

Other mutations at this position

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