Mutations

APP T719N

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891777 C>A
Position: (GRCh37/hg19):Chr21:27264089 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACC to AAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was first identified in a subject with a family history of autosomal-dominant Alzheimer’s disease (Scahill et al., 2013). This carrier was reported to have a “typical clinical presentation for FAD, with impairment of episodic memory progressing to global cognitive decline from [the] mid-late 40s.” The mutation was absent from 100 healthy, unrelated Caucasian control subjects.

Subsequently, the mutation was found in a subject enrolled in the Dominantly Inherited Alzheimer Network (DIAN) (Hsu et al., 2018). The proband became symptomatic at 45 years of age, the same age at which his or her parent was diagnosed with AD. The mutation was absent from the Exon Variant Server and ExAC databases.

This mutation was classified as probably pathogenic according to the algorithm employed by the DIAN Expanded Registry (Hsu et al., 2018).

Neuropathology

Unknown.

Biological Effect

In a heterologous expression system, the T719N mutation led to increased levels of Aβ42 and an elevated Aβ42:Aβ40 ratio, compared with wild-type APP (Hsu et al., 2018). Consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). A cryo-electron microscopy study of an APP fragment bound to PSEN1 indicated T719 helps anchor interactions between the two proteins via hydrogen bonding with PSEN1 G384 (Zhou et al., 2019; Jan 2019).

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.

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. T719N: 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.

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

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References

Paper Citations

  1. Scahill RI, Ridgway GR, Bartlett JW, Barnes J, Ryan NS, Mead S, Beck J, Clarkson MJ, Crutch SJ, Schott JM, Ourselin S, Warren JD, Hardy J, Rossor MN, Fox NC. Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations. J Alzheimers Dis. 2013 Jan 1;35(1):199-212. PubMed.
  2. Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.
  3. 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.

External Citations

  1. Jan 2019

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

Other mutations at this position

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Alzpedia

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