Mutations

APP G708G

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PS3, PM1, BS1, BS2, BP4
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr21:25891809 C>T
Position: (GRCh37/hg19):Chr21:27264121 C>T
dbSNP ID: rs148888161
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: GGC to GGT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This nucleotide variant, which is silent at the protein level, was first described in a Swedish study where it was identified in two of 12 Alzheimer's disease (AD) patients, in one of 60 non-AD patients, and in one of 30 healthy individuals (Balbín et al., 1992).

The variant was subsequently reported in a family with AD from the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). The proband and her deceased mother were affected, but only the proband was genotyped. The proband's age at onset was 60 and her mother's was 80. Three of the proband's siblings were identified as non-carriers and remained cognitively healthy at ages 68, 69, and 71. Of note, the proband had an APOE4/E3 genotype, while her three, non-carrier siblings were APOE3 homozygotes.  

The variant is found at a frequency of 0.002126 in the gnomAD variant database, with an allele count of 601 (v2.1.1, Oct 2021). Except for one homozygous individual, all carriers were heterozygotes, mostly with African or European ancestry. Moreover, in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, it was present with an allele count of two in a total of 954 alleles (HEX, Oct 2021).

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted slightly more Aβ42 and similar amounts of Aβ40 compared with cells expressing wild-type APP. The Aβ42/Aβ40 ratio was not significantly altered (Hsu et al., 2020). In silico analysis yielded a PHRED-scaled CADD score well below 20, predicting a low likelihood of deleteriousness (CADD v.1.6, Oct 2021). Hsu and colleagues classified this variant as a risk factor (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Benign*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

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

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. G708G: Increased Aβ42 moderately, without significantly altering Aβ42/Aβ40.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  G708G: Most carriers are of African or European descent.

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.

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: 17 Mar 2022

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References

Paper Citations

  1. Balbín M, Abrahamson M, Gustafson L, Nilsson K, Brun A, Grubb A. A novel mutation in the beta-protein coding region of the amyloid beta-protein precursor (APP) gene. Hum Genet. 1992 Jul;89(5):580-2. PubMed.
  2. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Other Citations

  1. HEX

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Balbín M, Abrahamson M, Gustafson L, Nilsson K, Brun A, Grubb A. A novel mutation in the beta-protein coding region of the amyloid beta-protein precursor (APP) gene. Hum Genet. 1992 Jul;89(5):580-2. PubMed.

Alzpedia

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