Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891762 A>T
Position: (GRCh37/hg19):Chr21:27264074 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant was identified in a Han Chinese family with early onset Alzheimer’s disease (AD; Peng et al., 2014). The proband’s first symptoms emerged at age 40 and included progressive memory loss, abnormal verbalization, and executive dysfunction. She was also described as sluggish and apathetic. Three of her siblings and her mother were also affected. Mean age at onset in the family was 46.6 years, ranging from 40 to 58 years.

Genetic analysis of the proband and two of her affected siblings revealed the presence of the K724 mutation. An unaffected sister who was also genotyped did not carry the mutation. However, she was only 50 years old, too young to qualify as a control for assessing co-segregation of the mutation with disease. The mutation was also absent from 50 age-matched controls, as well as from the gnomAD variant database (v4.1.0, Dec 2024).

Neuropathology
Neuropathological data are unavailable, but brain MRI of the proband revealed mild global brain atrophy and enlargement of the ventricles (Peng et al., 2014).

Biological Effect
When this variant was expressed in human embryonic kidney cells (HEK293), the Aβ42/Aβ40 ratio in conditioned media was 2.23 times higher than that of control cells expressing wildtype APP (Peng et al., 2014). The increased ratio was due to elevated Aβ42 levels.

Also of note, this variant may change the acetylation state of APP which could have implications for AD pathogenesis. Sirtuin 6 (SIRT6) deacetylates APP at three consecutive amino acids, the first being K724 (Cheng et al., 2024). Deacetylation of APP was tied to APP ubiquitination and degradation, and treatment of APP/PS1 mice with a SIRT6 activator reduced both amyloid pathology and memory deficits.

The variant's PHRED-scaled CADD score (26.4), which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.7, Dec 2024).

Peng and colleagues classified this variant as definitely pathogenic (Peng et al., 2014) according to the algorithm by Guerreiro et al. 2010.

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. K724M: Variant located at edge of mutational hot spot.

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.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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.

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

Last Updated: 16 Dec 2024

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References

Research Models Citations

Paper Citations

Peng XL, Hou L, Xu SH, Hua Y, Zhou SJ, Zhang Y, Zheng YP, Fu YH, Xu Q, Zhang LS, Wang J, Guan XT, He JS. Novel APP K724M mutation causes Chinese early-onset familial Alzheimer's disease and increases amyloid-β42 to amyloid-β40 ratio. Neurobiol Aging. 2014 Nov;35(11):2657.e1-2657.e6. Epub 2014 Jun 14 PubMed.
Cheng R, Bai N, Liu S, Zhao X, Jiang B, Guo W, Cao S, Liu J, Li N, Li X, Wu X, Yi F, Wang Z, Guo Q, Wei J, Bai M, Jiang X, Song X, Wang Z, Miao Q, Wang D, Di Y, Liu H, Cao L. The deacetylase SIRT6 reduces amyloid pathology and supports cognition in mice by reducing the stability of APP in neurons. Sci Signal. 2024 Dec 10;17(866):eado1035. Epub 2024 Dec 10 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 K724M

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