Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, 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 AAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This variant was identified in a 53-year-old Chinese man with early onset Alzheimer’s disease (Liang et al., 2023). His symptoms, emerging at age 52, included short-term memory loss and involuntary tremors. He had an APOE3/E4 genotype. His mother and older sister also experienced memory impairment at a similar age. The variant was reported as co-segregating with disease. However, the number of genotyped family members, and whether at least one unaffected non-carrier was included in this analysis, were not specified.

This variant was absent from the gnomAD variant database (v2.1.1, Oct 2023).

Neuropathology
Neuropathological data are unavailable, but MRI scans of the proband revealed enlarged ventricles and sulci indicative of generalized cerebral atrophy (Liang et al., 2023). Moreover, PET imaging showed diffuse amyloid deposition in the cortex, particularly in occipital areas. Biomarkers in the cerebrospinal fluid were consistent with AD.

Biological Effect
Although experimental data for this variant are unavailable, the substitution is located at the α-secretase cleavage site in APP and K687N (A>T) was found to increase Aβ40 and Aβ42 production, while reducing production of sAPP and especially sAPPα (Kaden et al., 2012). The mutant Aβ42 peptide was less toxic to neuroblastoma cells than wildtype Aβ42, but was highly toxic when mixed with equimolar amounts of the wildtype peptide (as expected to happen in heterozygous carriers). Similarly, although the mutant Aβ peptide formed predominantly low-n oligomers in vitro, when mixed with wild-type Aβ it aggregated into high-n oligomers. The Aβ K16N peptide was also much less efficiently degraded by the protease neprilysin.

Overall, in silico analyses predicted this variant disrupts protein function. K687 is evolutionarily conserved and a structural model suggested impaired interaction between APP and nicastrin in the γ-secretase complex (Liang et al., 2023). Moreover, Polyphen2 classified it as probably damaging and SIFT as deleterious. Also, its PHRED-scaled CADD score was above 20 (24.9), also suggesting a damaging effect (CADD v1.6, 2023). However, Liang and colleagues reported a lower CADD score of 11.82.

The variant was classified by Liang and co-workers as pathogenic/likely pathogenic based on the ACMG-AMP guidelines (Richards et al., 2015).

Functional Consequences

Unknown, but K687N (A>T) increased Aβ40 and Aβ42, and when mixed with wildtype Aβ, generated large oligomers; highly toxic in cells. Reduced degradation by neprilysin.

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. K687N (A>C): Functional studies of K687N (A>T) indicate a damaging effect.

PM1-M

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

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-P

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. K687N (A>C): Reported as co-segregating with disease, but the number of genotyped family members and whether at least one unaffected non-carrier was included in this analysis, were not specified.

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: 01 Aug 2023

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References

Mutations Citations

Paper Citations

Liang Z, Wu Y, Li C, Liu Z. Clinical and genetic characteristics in a central-southern Chinese cohort of early-onset Alzheimer's disease. Front Neurol. 2023;14:1119326. Epub 2023 Mar 27 PubMed.
Kaden D, Harmeier A, Weise C, Munter LM, Althoff V, Rost BR, Hildebrand PW, Schmitz D, Schaefer M, Lurz R, Skodda S, Yamamoto R, Arlt S, Finckh U, Multhaup G. Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers. EMBO Mol Med. 2012 Jul;4(7):647-59. PubMed.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

APP K687N (A>C)

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