Mutations

APP c.-265C>A (-118C>A)

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26170885 C>A
Position: (GRCh37/hg19):Chr21:27543203 C>A
Transcript: NM_000484
dbSNP ID: NA
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 individual with Alzheimer’s disease (Theuns et al., 2006). Age at onset was 50 and age at death was 64. The carrier did not have a family history of AD. Their APOE genotype was APOE3/E4. Of note, the carrier was a compound heterozygote carrying a second, more distal variant: c.-1897G>A (a.k.a., -1750G>A).

Both variants were absent from the gnomAD variant database (v2.1.1, March 2023).

Biological Effect
In human neuroblastoma (SH-SY5Y) cells, a luciferase reporter including the APP promoter with the c.-265C>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.-265C>A. This revealed a protein complex with a higher affinity for the mutant 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.-265C>A substitution abolishes a predicted repressive binding site for the transcription factor AP-2 which controls neural gene expression in mammals. It also abolishes a predicted binding site for transcriptional repressor HES-1, a regulator of several steps in the development of the nervous system.

c.-265C>A’s PHRED-scaled CADD score, which integrates diverse information in silico, was 8.58, failing to reach the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, March 2023).

In silico analysis of the carrier’s second APP variant, c.-1897G>A, did not reveal any putative transcription factor binding sites and was therefore not functionally assessed.

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. c.-265C>A (-118C>A): Located in the APP promoter, within two putative transcription binding sites.

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.

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: 20 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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