Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891793 A>G
Position: (GRCh37/hg19):Chr21:27264105 A>G
dbSNP ID: rs63750643
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to GCA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was first reported in a three-generation Iranian pedigree with nine documented affected individuals and an average age of onset of approximately 55 years. The common feature of all the affected members of this family was progressive dementia consistent with AD, although motor apraxia was also observed in some cases. The reporting authors noted that the age at onset in this family was considerably older than the age reported for APP T714I, presumably because alanine causes less disruption to the transmembrane structure than isoleucine (Pasalar et al., 2002). The mutation was identified in two affected siblings and was absent from an unrelated, healthy individual.

This mutation has been found in two additional studies. One was a Polish individual with Alzheimer's disease. In this patient, onset was at 44 years and the disease progressed rapidly, leading to severe memory impairment and other cognitive and behavioral deficits within four years (Zekanowski et al., 2003). A different clinical picture was associated with this mutation in another, unrelated individual who was diagnosed with AD following a long prodromal phase (eight years of isolated amnesia). The clinical presentation in this individual was atypical in that it was also characterized by autonomic failure and seizures (Lindquist et al., 2008).

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

Neuropathology

The neuropathology associated with this mutation is not well characterized, but neuroimaging in one patient showed progressive cortical atrophy and white matter lesions (Lindquist et al., 2008).

Biological Effect

A survey of Aβ peptides produced from APP carrying this variant, referred to as A43T, revealed an increase in the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway relative to the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway and inefficient processing of longer peptides (Devkota et al., 2021, Feb 2021 news). Levels of Aβ42, Aβ46, and Aβ48—the latter two being membrane-anchored and also potentially pathogenic—were increased.

Consistent with these findings, a cryo-electron microscopy study of a fragment of APP bound to presenilin 1 suggests T714 is important for the generation of Aβ peptides. Closely apposed to PSEN1 M146, T714 appears to be involved in the recognition of APP by γ-secretase (Zhou et al., 2019; Jan 2019 news). Moreover, the T714A variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. T714A: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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. T714A: 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: 29 Sep 2023

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References

News Citations

Paper Citations

Pasalar P, Najmabadi H, Noorian AR, Moghimi B, Jannati A, Soltanzadeh A, Krefft T, Crook R, Hardy J. An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). Neurology. 2002 May 28;58(10):1574-5. PubMed.
Zekanowski C, Styczyńska M, Pepłońska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haładyna B, Kotapka-Minc S, Mikkelsen S, Pfeffer A, Barczak A, Łuczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Łaczkowski J, Sobów T, Kuźnicki J, Barcikowska M. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
Lindquist SG, Nielsen JE, Stokholm J, Schwartz M, Batbayli M, Ballegaard M, Erdal J, Krabbe K, Waldemar G. Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation. J Neurol Sci. 2008 May 15;268(1-2):124-30. 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.

Mutations

APP T714A (Iranian)

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