Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25897578 A>C
Position: (GRCh37/hg19):Chr21:27269890 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAA to CAA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This variant was first reported in a whole-exome sequencing study of Chinese Alzheimer’s cases with a family history consistent with autosomal dominant inheritance (Jiang et al., 2019). The variant was seen in two unrelated families. In the first family, genotype data was available only from the proband. In the second family, both the proband and an affected brother were found to be carriers of the variant; the proband’s son (age not reported) did not carry the variant and was cognitively healthy. The ages of onset of the carriers ranged from 52 to 63 years.

Subsequently, the variant was found to segregate with an imaging endophenotype in a Chinese pedigree (Yi et al., 2020). Twenty family members underwent neuroimaging studies, and white-matter hyperintensities were found in 12 individuals. Pedigree analysis was consistent with an autosomal-dominant pattern of inheritance. Eight affected individuals were genotyped, and all are heterozygous carriers of the APP K687Q mutation. None of the eight family members with normal imaging findings carry the mutation. Six of the mutation carriers and three of the noncarriers showed some degree of cognitive dysfunction, as assessed by the MMSE, MoCA, or Mini-Cog. The authors of this study describe the imaging abnormalities in this family as similar, but not identical, to those seen in cases of cerebral amyloid angiopathy, but note that the clinical manifestations are less severe than in CAA.

The K687Q variant was not found in the ExAC, gnomAD, or 1000 Genomes Project databases, or in 500 ethnically and age-matched controls (Jiang et al., 2020).

Biological Effect

A yeast cell-based assay to monitor Aβ aggregation revealed this substitution, which lies within the Aβ peptide, accelerates nucleation compared with the wildtype peptide (Seuma et al., 2022, suppl 3). Also of note, the mutation is located at the α-secretase cleavage site of APP. It was predicted to be probably damaging by PolyPhen-2 and tolerated by SIFT, and was classified as likely pathogenic using the American College of Medical Genetics and Genomics criteria (Jiang et al., 2020).

Pathogenicity

Alzheimer's Disease : Pathogenic

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. Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
2. Yi Y, Xiaobin Y, Hui C, Yufa Z, Qiaowei Z, Xingyue H, Huaying C. An APP mutation family exhibiting white matter hyperintensities and cortical calcification in East China. Neurol Sci. 2020 Oct;41(10):2921-2928. Epub 2020 Apr 28 PubMed.
3. Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. PubMed.

Further Reading

No Available Further Reading