Mutations

APP G342S

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS4, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27372339 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to AGC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 7

Findings

This variant was found in five individuals with Alzheimer’s disease (AD) in a case-control study including 1154 patients of Chinese ancestry (Xiao et al., 2022). It was absent from 2403 controls.

In the gnomAD variant database, this variant was reported only in East Asians, including 23 heterozygotes with an allele frequency of 0.0012 (gnomAD v2.1.1, Jan 2023). The global frequency was 0.000081.

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 22.5, suggesting a damaging effect (CADD v.1.6, Jan 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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. G342S: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  G342S: All carriers were of East Asian ancestry.

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

Last Updated: 11 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.

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