Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891787 A>G
Position: (GRCh37/hg19):Chr21:27264099 A>G
dbSNP ID: rs63750399
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to GTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 15

Findings

This mutation was first reported in an American patient diagnosed with probable Alzheimer's disease. She had a family history of dementia with a mean age of onset of about 53 years (Eckman et al., 1997).

This mutation was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology

MRI of the patient showed diffuse cortical atrophy, most prominant in the left anterior temporal lobe (Eckman et al., 1997).

Biological Effect

Initial studies showed that, when expressed in HEK293 or CHO cells, this variant caused an approximately twofold increase in Aβ42 or Aβ43 and a significant increase in the Aβ42(43)/Aβ40 ratio (Eckman et al., 1997). Subsequent cell-based studies reported similar increases specifically in Aβ42 and in the ratio of Aβ42(43)/Aβ40 but the elevations were modest compared with other pathogenic APP variants (De Jonghe et al., 2001; Xu et al., 2016). Decreased ε-cleavage was also observed (Xu et al., 2016).

A survey of the peptides produced by purified γ-secretase in vitro, however, failed to detect a change in the Aβ42/Aβ40 ratio, but found increased levels of Aβ43 (Devkota et al., 2021, Feb 2021 news). This study also revealed decreased activity of the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway, with increased Aβ48 levels, reflecting a shift in ε-cleavage towards Aβ48 and inefficient processing of longer, membrane-anchored Aβ peptides that may be pathogenic. Levels of total APP intracellular domain (AICD) were similar to those of wild-type APP.

Of note, the interaction of the V715-I176 segment of APP with the catalytic unit of γ-secretase, PSEN1, has been described in a cryo-electron microscopy study, including how it differs from that of PSEN1 with the Notch substrate (Zhou et al., 2019; Jan 2019 news). Also, a study using molecular dynamics simulations suggested I716, together with V715, serve to anchor APP at the PSEN1 internal docking site, a region distinct from the catalytic center, that is essential for substrate positioning and stabilization (Chen and Zacharias 2022).

This variant's PHRED-scaled CADD score was above 20, suggesting a damaging effect (CADD v1.6, 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-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. I716V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

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: 10 Nov 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

Paper Citations

Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, Graff-Radford N, Hinder P, Yager D, Zenk B, Refolo LM, Prada CM, Younkin SG, Hutton M, Hardy J. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997 Nov;6(12):2087-9. PubMed.
De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B. Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001 Aug 1;10(16):1665-71. PubMed.
Xu TH, Yan Y, Kang Y, Jiang Y, Melcher K, Xu HE. Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to γ-secretase cleavage and the Aβ42/Aβ40 ratio. Cell Discov. 2016;2:16026. Epub 2016 Aug 23 PubMed.
Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.

Mutations

APP I716V (Florida)

Quick Links