Mutations

APP T600M

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr21:25911851 C>T
Position: (GRCh37/hg19):Chr21:27284163 C>T
dbSNP ID: rs200088099
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 14

Findings

This variant in APP was detected in one out of 376 control cases obtained from the KORA-Age cohort, based in Germany (Schulte et al., 2015). Limited information is available on this subject, but according to a description of the cohort as a whole, all individuals were Caucasian and cognitively healthy at age 65 or older (Schulte et al., 2012).

In the gnomAD database, 51 heterozygous carriers are reported, most from the Latino/Admixed American population (gnomAD version 2.1.1, Oct 2021). Total frequency was 0.0002028.

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted less Aβ40 compared with cells expressing wild-type APP, but neither the secretion of Aβ42 nor the Aβ42/Aβ40 ratio were significantly altered (Hsu et al., 2020). However, the PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, predicting a deleterious effect (CADD v.1.6, Oct 2021). Hsu and colleagues classified this variant as not pathogenic (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Benign*

*No reported carrier with AD.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  T600M: Most carriers are of Latino/Admixed American 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.

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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

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.

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.

Alzpedia

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.