Overview

Pathogenicity: Alzheimer's Disease : Benign, Parkinson's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: Alzheimer's Disease, Parkinson's Disease
Position: (GRCh38/hg38):Chr21:25911855 G>A
Position: (GRCh37/hg19):Chr21:27284167 G>A
dbSNP ID: rs140304729
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to AAA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 14

Findings

This variant has been found in individuals with neurodegenerative disease, as well as in healthy controls. It was initially reported in an exome-sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls without neuropathology. The variant was detected in one Caucasian control who was at least 60 years of age at death. APOE genotype was E3/E4. Further clinical details were not available (Sassi et al., 2014).

The variant was subsequently detected in one out of 188 cases with Parkinson’s disease, two out of 188 cases with PD with dementia, and one out of 376 controls (Schulte et al., 2015). It was also detected by whole-exome sequencing in two of 424 French people with early onset AD. Clinical details were not reported (Nicolas et al., 2015).

In the gnomAD database, 421 heterozygous carriers and one homozygote are reported (version 2.1.1, Oct 2021). Most of these individuals are from European descent, but the variant is also present in other populations. Total frequency was 0.001492. The variant was also found 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, 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 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).

Sassi and colleagues reported a possibly damaging prediction from in silico analysis and 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). The variant was classified as a benign polymorphism according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014) and as "not pathogenic" by Hsu and colleagues (Hsu et al., 2020).

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.

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References

Paper Citations

1. 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.
2. 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.
3. Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard AC, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Maréchal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Sauvée M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
4. 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.
5. 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.

Other Citations

1. HEX

Further Reading

No Available Further Reading