Mutations

PSEN1 H214R

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659444 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to CGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a Chinese family including nine members spanning two generations affected by early onset dementia (Li et al., 2019). The proband presented with memory decline, mood alterations, and behavioral changes at 41 years of age. His mother, three siblings of his mother, and three of his siblings developed similar symptoms at approximately 40 years of age. In addition to the proband, the proband’s mother, a sibling, and an uncle, all of whom were affected, carried the mutation. The mutation was absent from 200 Chinese healthy controls and two genetic variant databases (ExAC and 1000 Genomes).

The variant was also identified in a Han Chinese woman with AD and a family history of dementia (Mao et al., 2021). Her age at onset was 45 years. She had an APOE3/E3 genotype.

Neuropathology
Although neuropathological data are unavailable, a brain MRI of one carrier showed mild white matter demyelination of the frontal and parietal lobes, with no apparent atrophy of the cerebral cortex or hippocampus (Li et al., 2019).

Biological Effect
The biological effects of this variant are unknown, but several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, MutPred2, SNAP, and Reve) predicted this variant is damaging (Li et al., 2019, Xiao et al., 2021, Mao et al., 2021).

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).

Mao and colleagues classified the variant as likely pathogenic (Mao 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.

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. H214R: Variant is at edge of a mutational hot spot; cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 15 Nov 2022

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References

News Citations

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

Paper Citations

  1. Li YS, Yang ZH, Zhang Y, Yang J, Shang DD, Zhang SY, Wu J, Ji Y, Zhao L, Shi CH, Xu YM. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. PubMed.
  2. Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. 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.
  4. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Li YS, Yang ZH, Zhang Y, Yang J, Shang DD, Zhang SY, Wu J, Ji Y, Zhao L, Shi CH, Xu YM. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. PubMed.

Other mutations at this position

View Table

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