Mutations

APP c.-681G>A (-534G>A)

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM1, BS1, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26171301 G>A
Position: (GRCh37/hg19):Chr21:27543619 G>A
dbSNP ID: rs187510057
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: 2kb upstream

Findings

This variant, located in the APP promoter, was identified in a Dutch patient with familial Alzheimer’s disease (Theuns et al., 2006). The carrier’s age at onset was 52 and they died at age 70. They had an APOE3/E4 genotype.

This variant was found at a frequency of 0.00096 in the gnomAD variant database (v2.1.1, March 2023). Twenty-eight of 30 heterozygotes were of European ancestry.

Biological Effect
In human neuroblastoma (SH-SY5Y) cells, a luciferase reporter including the APP promoter with the c.-681G>A variant revealed a nearly twofold increase in transcriptional activity compared with two variants found only in control individuals (p<0.001, Theuns et al., 2006). This increase in expression was comparable to that of AD patients with APP duplications known to be pathogenic.

In addition, the authors used electrophoretic mobility shift assays to probe the binding of proteins from nuclear extracts of SH-SY5Y cells to a 31-bp stretch of the APP promoter including c.-681G>A. Two major protein complexes were detected, with the smaller having lower affinity for the A allele than the G allele. Also of note, The c.-681G>A substitution created a putative binding site for Oct1, a member of the POU domain family of transcription factors which play a role in neuronal development, and in particular, neurite outgrowth. 

Interestingly, increased transcription was not observed in human embryonic kidney cells (HEK293). Moreover, no differences in APP expression were detected in lymphoblasts from mutation carriers compared with those of controls as assessed by PCR.

This variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 7.68, failing to reach the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, March 2023).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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. c.-681G>A (-534G>A): Located in the APP promoter, predicted to create a new transcription binding site.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  c.-681G>A (-534G>A): Most carriers were of European ancestry.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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 Mar 2023

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References

Mutation Position Table Citations

  1. APP Duplication - Mutations

Paper Citations

  1. Theuns J, Brouwers N, Engelborghs S, Sleegers K, Bogaerts V, Corsmit E, De Pooter T, van Duijn CM, De Deyn PP, Van Broeckhoven C. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet. 2006 Jun;78(6):936-46. Epub 2006 Apr 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Theuns J, Brouwers N, Engelborghs S, Sleegers K, Bogaerts V, Corsmit E, De Pooter T, van Duijn CM, De Deyn PP, Van Broeckhoven C. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet. 2006 Jun;78(6):936-46. Epub 2006 Apr 10 PubMed.

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