Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891785 C>G
Position: (GRCh37/hg19):Chr21:27264097 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was identified in a German individual of European descent diagnosed with early onset Alzheimer’s disease (Blauwendraat et al., 2015). This individual developed progressive memory impairment and orientation deficits at age 64. Other symptoms included rapid eye movement sleep behavior disorder and behavioral changes. Death occurred at age 70. This was a case of apparently sporadic AD; family history was negative for neurological disease. This individual also carried a novel mutation (A181T) in the gene CHMP2B, which encodes a component of the endosomal sorting complex, ESCRT-III.

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

Neuropathology

Unknown. MRI showed mild bilateral hippocampal atrophy.

Biological Effect

Unknown. Although some in silico algorithms predicted this mutation is damaging (Blauwendraat et al., 2015), its PHRED-scaled CADD score, which integrates diverse information in silico, did not quite reach 20, a threshold often used to predict deleteriousness (CADD v.1.6, Oct 2021).

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).

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.

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. I716M: 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.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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: 19 Oct 2023

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References

News Citations

Paper Citations

Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016 Jan;37:208.e11-7. Epub 2015 Sep 30 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 I716M

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