Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM1, BS1, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26171136 C>G
Position: (GRCh37/hg19):Chr21:27543454 C>G
dbSNP ID: rs539645405
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: 2

Findings

This variant, located in the APP promoter, was identified in a Dutch patient and a Belgian patient with familial Alzheimer’s disease (Theuns et al., 2006). The Dutch carrier’s age at onset was 63 and they died at an unknown age. The Belgian’s age at onset was 61 and they were 75 years old at the time of the study. The Dutch individual had an APOE3/E4 genotype, while the Belgian was homozygous for APOE4. The two may have had a common ancestor because haplotype analysis identified shared polymorphisms at five neighboring sites in the APP region, although the same haplotype was observed in one percent of control individuals.

This variant was found at a frequency of 0.00013 in the gnomAD variant database (v2.1.1, March 2023). Three of four heterozygotes were of non-Finnish European ancestry.

Biological Effect
In human neuroblastoma (SH-SY5Y) cells, a luciferase reporter including the APP promoter with the c.-516C>G 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.-516C>G. The major protein complex showed decreased binding affinity to the mutant sequence and a slight shift in mobility compared with the control sequence.

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. Consistent with these observations, the c.-516C>G substitution abolishes a predicted repressive binding site for the transcription factor AP-2 which controls neural gene expression in mammals.

c.-516C>G PHRED-scaled CADD score, which integrates diverse information in silico, was 6.33, 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.

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References

Mutation Position Table Citations

1. APP Duplication - Mutations 8 Mar 2023

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