Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27269905 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: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This mutation was identified in a single patient in Leuven, Belgium. In her late 40s the patient developed symptoms of depression, followed by progressive cognitive decline (Zhou et al., 2011).

The variant is absent from the gnomAD variant database (v2.1.1, 2021).

Neuropathology

MRI revealed bilateral hippocampal volume loss in the patient. Cortical PiB uptake was also observed.

Biological Effect

This mutation at the β' site in APP shifts BACE1 cleavage toward the β-site and causes a significant increase in total Aβ and in Aβ42/40 levels. In addition, a yeast cell-based assay to monitor Aβ aggregation suggested this substitution accelerates nucleation compared with the wildtype peptide (Seuma et al., 2022, suppl 3).

This variant's PHRED-scaled CADD score was above 20, suggesting a damaging effect (CADD v1.6, 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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.

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.

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: 17 Jul 2023

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References

Paper Citations

Zhou L, Brouwers N, Benilova I, Vandersteen A, Mercken M, Van Laere K, Van Damme P, Demedts D, Van Leuven F, Sleegers K, Broersen K, Van Broeckhoven C, Vandenberghe R, De Strooper B. Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation. EMBO Mol Med. 2011 May;3(5):291-302. Epub 2011 Apr 15 PubMed.
Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. PubMed.

Mutations

APP E682K (Leuven)

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