Mutations

APP c.-111G> C

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BA1, BS1, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26170731 C>G
Position: (GRCh37/hg19):Chr21:27543049 C>G
dbSNP ID: rs459543
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 1, 5'UTR

Findings

This variant in the 5’ untranslated region of APP mRNA, was described in a case-control study of 1154 Alzheimer’s disease (AD) patients and 2403 controls of Chinese ancestry (Xiao et al., 2022). It was not significantly associated with AD risk (OR=0.97, 95% CI 0.85-1.11, p = 0.61). Moreover, although it was “nominally correlated” with Aβ42 levels in cerebrospinal fluid (β=-157.2, p=0.0079), the correlation did not survive Bonferroni correction.

In the gnomAD variant database, this variant was found at a global frequency of 0.086 (gnomAD v2.1.1, Jan 2023). In East Asians, it was approximately twice as high (0.19), similar to the frequency reported by Xiao and colleagues (0.18 in cases; 0.19 in controls). Also of note, compared with its frequency in non-Finnish Europeans in the gnomAD database (0.028), the variant was relatively abundant (0.037 frequency; 16/432 alleles) in the Healthy Exomes database (HEX), a database of variants from Caucasians aged 60 or older who did not have a diagnosis of a neurodegenerative disease or disease-associated neuropathology at the time of death (HEX, Jan 2023).

Neuropathology
Neuropathological data are unavailable.

Biological Effect
The biological effect of this variant is unknown but its PHRED-scaled CADD score, which integrates diverse information in silico, was low (10.41), suggesting it does not have a damaging effect (CADD v.1.6, Jan 2023).

Pathogenicity

Alzheimer's Disease : Benign

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

BA1

Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database. c.-111G> C: This variant was found in approximately 9% of individuals worldwide, 19% of East Asians, and 2.8% of Europeans.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. c.-111G> C: This variant was found in about 4% of Caucasians in the Healthy Exomes (HEX) database.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 10 Jan 2023

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References

Paper Citations

  1. Xiao X, Liu H, Zhou L, Liu X, Xu T, Zhu Y, Yang Q, Hao X, Liu Y, Zhang W, Zhou Y, Wang J, Li J, Jiao B, Shen L, Liao X. The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population. CNS Neurosci Ther. 2023 Jan;29(1):122-128. Epub 2022 Oct 10 PubMed.

Other Citations

  1. HEX

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Xiao X, Liu H, Zhou L, Liu X, Xu T, Zhu Y, Yang Q, Hao X, Liu Y, Zhang W, Zhou Y, Wang J, Li J, Jiao B, Shen L, Liao X. The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population. CNS Neurosci Ther. 2023 Jan;29(1):122-128. Epub 2022 Oct 10 PubMed.

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