Mutations

APP R468H

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS2, BS3
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr21:27347438 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 11

Findings

This APP variant was detected in one control case obtained from the KORA-Age cohort, based in Germany (Schulte et al., 2015). Specific information about this individual is not available, but participants in the cohort are described as Caucasian and cognitively healthy at age 65 or older (Schulte et al., 2012).

This variant was also found in the gnomAD at a frequency of 0.00001593 and an allele count of four, with three Finnish and one South Asian carriers (gnomAD v2.1.1, Oct 2021). 

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and Aβ40 compared with cells expressing wild-type APP, resulting in a similar Aβ42/Aβ40 ratio (Hsu et al., 2020). However, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a 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.

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.

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.

BS3-S

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

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

Last Updated: 15 Mar 2022

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References

Paper Citations

  1. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  2. Schulte EC, Mollenhauer B, Zimprich A, Bereznai B, Lichtner P, Haubenberger D, Pirker W, Brücke T, Molnar MJ, Peters A, Gieger C, Trenkwalder C, Winkelmann J. Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease. Neurogenetics. 2012 Aug;13(3):281-5. Epub 2012 Jun 16 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.

External Citations

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

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.

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