Mutations

APP D332G

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26000053 A>G
Position: (GRCh37/hg19):Chr21:27372368 A>G
dbSNP ID: rs773998162
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GGC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 7

Findings

This variant was identified in a whole-exome sequencing study of Chinese Alzheimer’s cases with a family history consistent with autosomal-dominant inheritance (Jiang et al., 2019). The carrier was a 47-year-old man who exhibited impairments in memory, visual-construction abilities, and arithmetic skills, as well as changes in personality. MRI showed atrophy of the hippocampus and of the temporal and parietal lobes. The carrier’s mother showed similar cognitive deficits, but her genotype is unknown.

The variant was also reported in two AD patients from a case-control study including 1154 AD patients and 2403 controls of Chinese ancestry (Xiao et al., 2022).

The D332G variant was not found in the 1000 Genomes Project database or in 500 ethnically and age-matched controls (Jiang et al., 2019). Two heterozygous carriers were found among the East Asian population in gnomAD (v2.1.1, searched 2020-10-14).

Biological Effect

The biological effect of the aspartate-to-glycine substitution has not been tested directly yet. The D3332G mutation is predicted to be damaging by PolyPhen-2 but tolerated by SIFT (Jiang et al., 2019). Its PHRED-scaled CADD score, which integrates diverse information in silico, was 22.8, 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.

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.

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.

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. 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.
  2. 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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