Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3, BS2, BS3
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr21:25955716 G>A
Position: (GRCh37/hg19):Chr21:27328030 G>A
dbSNP ID: rs201547994
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCA to ACA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 12

Findings

This variant 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).

Two heterozygous carriers of this variant were found in the gnomAD database (version 2.1.1, Oct 2021), one Latino/Admixed American and one European (non-Finnish).

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 PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting 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 : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it is not classified by Alzforum because no affected carriers have been reported, and the variant is absent, or very rare, in the gnomAD database.

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.

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

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.
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.
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.

Mutations

APP A500T

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