Mutations
APP K724N (Belgian)
Other Names: Belgian
Quick Links
Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PS3, PM1, PM2, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891761 G>C
Position: (GRCh37/hg19):Chr21:27264073 G>C
dbSNP ID: rs63750151
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: AAG to AAC
Reference
Isoform: APP Isoform APP770 (770 aa)
Genomic
Region: Exon 17
Findings
This mutation, which is just outside the transmembrane domain of APP, was first described in a Belgian patient who began having memory problems at the age of 55 and fulfilled the criteria of probable AD. She had a family history of dementia. Her father was diagnosed with Pick's disease at the age of 52 and died without autopsy at the age of 56. The proband's symptoms included progresive impairment of episodic memory and executive functioning. Other symptoms included anxiety, depression, and apathy (Theuns et al., 2006).
This mutation was absent from the gnomAD variant database (v2.1.1, Oct 2021).
Neuropathology
The mutation carrier had significantly more amyloid across the cerebral cortex than control subjects as measured by PiB-PET (Theuns et al., 2006).
Biological Effect
A significantly increased Aβ42/Aβ40 ratio was measured in the conditioned media of K724N-transfected HEK293T cells. A similar increase was measured in primary mouse neurons due to an increase in Aβ42 and a decrease in Aβ40 (Theuns et al., 2006). Moreover, 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).
Pathogenicity
Alzheimer's Disease : Not Classified*
*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, 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.
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. K724N: 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: 22 Feb 2022
References
Paper Citations
- Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, Brouwers N, Van den Broeck M, Vennekens K, Corsmit E, Cruts M, De Strooper B, Van Broeckhoven C, Vandenberghe R. Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006 Sep;27(9):888-96. PubMed.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, Brouwers N, Van den Broeck M, Vennekens K, Corsmit E, Cruts M, De Strooper B, Van Broeckhoven C, Vandenberghe R. Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006 Sep;27(9):888-96. PubMed.
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