Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198099 G>A
Position: (GRCh37/hg19):Chr14:73664807 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to AAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in three Malaysian siblings whose family was affected by familial early onset Alzheimer’s disease with prominent behavioral changes and atypical features (Ch’ng et al., 2015). The reported five-generation pedigree shows seven family members with dementia, behavioral change (e.g., aggression), and parkinsonism. The female proband developed symptoms at age 48, starting with mood and behavior changes. She also presented with visual and auditory hallucinations and myclonic jerks. Two of her siblings were also affected by dementia with behavioral changes (onset at age 55 and 57, respectively). Their father had dementia when he died of cancer at age 71. The mutation segregated with disease: it was present in the three affected siblings and absent in 10 unaffected family members.

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

Neuropathology

Neuropathological data are unavailable, but MRI of the proband showed generalized brain atrophy including atrophy of the hippocampus.

Biological Effect

The biological effects of this mutation are unknown, but several in silico analyses (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), and additional pathogenic mutations at this site have been reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, revealed that E280 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for γ-secretase cleavage (Zhou et al., 2019; Jan 2019 news). The carboxylate side chain of E280 makes a bifurcated H-bond to the hydroxyl groups of Y154 and Y159, both from transmembrane domain 2 of PSEN1. These interactions are buttressed by two additional H-bonds from R278 to E280 and Y159.

Pathogenicity

Alzheimer's Disease : 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-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. E280K: Variant is in a mutational hot spot and 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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. E280K: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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: 22 Feb 2022

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References

News Citations

Paper Citations

Ch'ng GS, An SS, Bae SO, Bagyinszky E, Kim S. Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. Neuropsychiatr Dis Treat. 2015;11:2315-22. Epub 2015 Sep 8 PubMed.
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.
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.

Mutations

PSEN1 E280K

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