Mutations

APP A235V

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS3, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26022001 C>T
Position: (GRCh37/hg19):Chr21:27394317 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GTT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 6

Findings

This APP variant was identified in one of 424 French people with early onset AD by whole-exome sequencing (Nicolas et al., 2015). Given that it is located in exon 6, the A235V variant is considered unlikely to be pathogenic.

This variant was found in the gnomAD variant database, where it was particularly prevalent in the South Asian population (21 alleles), with additional carriers in the European, non-Finnish population (12 alleles) (gnomAD v2.1.1, Oct 2021).

Neuropathology

Unknown

Biological Effects

Mouse neuroblastoma cells expressing this variant secreted approximately half the amount of Aβ42 and Aβ40 compared with cells expressing wild-type APP. The Aβ42/Aβ40 ratio was similar to controls (Hsu et al., 2020). The authors noted this effect suggests this variant may confer resilience to AD.

The variant's PHRED-scaled CADD score, which integrates diverse information in silico, was below 20, suggesting a non-deleterious effect (CADD v.1.6, Oct 2021).

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  A235V: Most carriers are of South Asian descent.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

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: 11 Mar 2022

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References

Paper Citations

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.