Overview

Pathogenicity: Alzheimer's Disease : Benign, Parkinson's Disease Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: BS1, BS2, BS3, BP4
Clinical Phenotype: None, Parkinson's Disease Dementia
Position: (GRCh38/hg38):Chr21:26051060 C>T
Position: (GRCh37/hg19):Chr21:27423376 C>T
dbSNP ID: rs149995579
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 5

Findings

This variant in APP was found in an exome sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls without neuropathology at the time of their deaths. The variant was detected in one Caucasian control who was at least 60 years old at death. Further clinical details were not available. APOE genotype was ε3/ε4 (Sassi et al., 2014).

This variant was also detected in an individual with apparently idiopathic Parkinson’s disease with dementia (Schulte et al., 2015). This individual developed symptom onset at age 70, starting with bradykinesia and resting tremor. During an eight-year-disease duration, other symptoms included rigidity, postural instability, and dementia.

The variant was found in the gnomAD variant database at a frequency of 0.0001114 and an allele count of 28, with 24 of the alleles belonging to individuals of European descent (gnomAD v2.1.1, Oct 2021). 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 one in a total of 954 alleles (HEX, Oct 2021).

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of both Aβ42 and Aβ40 resulting in a similar Aβ42/Aβ40 ratio compared with cells expressing wild-type APP (Hsu et al., 2020).

In silico, this variant has been predicted to be "tolerated," and consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, is < 20. It was classified as not pathogenic (Hsu et al., 2020), and as a benign polymorphism according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014).

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.

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.

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

Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Al-Sarraj S, Niblock M, Gallo JM, Adnan J, Killick R, Brown KS, Medway C, Lord J, Turton J, Bras J, Alzheimer's Research UK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 PubMed.
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.
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.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Mutations

APP A201V

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