Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264104 C>T
dbSNP ID: rs63750973
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to ATA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 2

Findings

This mutation involves amino acid position 714 in APP and is located at a site of γ-secretase cleavage. It was first reported in an Austrian family known as AD156 whose members displayed an autosomal-dominant form of early onset Alzheimer's disease. This mutation appears to produce a particularly aggressive form of AD that had a mean onset age of approximately 34 years in the Austrian family (Kumar-Singh et al., 2000). Two affected siblings carried the mutation, but not their unaffected father, indicating cosegregation with disease.

This mutation was also identified in an American kindred of African descent. Affected family members were diagnosed with AD with an unusually early onset (early 30s), similar to that reported in the Austrian family. Clinical findings for this family included a rapidly progressive dementia with early memory loss, seizures, myoclonus, parkinsonism, spasticity, and behavioral symptoms including pathologic laughter (Edwards-Lee et al., 2005).

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

Neuropathology

Postmortem analysis of members of the Austrian family showed extensive neuronal loss, diffuse gliosis, and amyloid plaques and neurofibrillary tangles consistent with a diagnosis of AD. Aβ40 was notably absent from amyloid deposits in the brain, and the deposits were largely in the form of "cloudy" diffuse plaques with a non-neuritic cotton-wool appearance (Kumar-Singh et al., 2000).

Biological Effect

This mutation is thought to affect APP processing by γ-secretase and alters the Aβ42/Aβ40 ratio approximately 11-fold, simultaneously increasing Aβ42 and decreasing Aβ40 secretion (Kumar-Singh et al., 2000).

Consistently, 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.

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.

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.

PP1-M

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. T714I: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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

News Citations

Paper Citations

Kumar-Singh S, De Jonghe C, Cruts M, Kleinert R, Wang R, Mercken M, De Strooper B, Vanderstichele H, Löfgren A, Vanderhoeven I, Backhovens H, Vanmechelen E, Kroisel PM, Van Broeckhoven C. Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease. Hum Mol Genet. 2000 Nov 1;9(18):2589-98. PubMed.
Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. 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 T714I (Austrian)

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