Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891790 G>A
Position: (GRCh37/hg19):Chr21:27264102 G>A
dbSNP ID: rs63750734
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was first reported in a two-generation family of Italian origin with three affected siblings fulfilling NINCDS-ADRDA criteria for probable AD. Affected individuals displayed memory problems with an age of onset ranging from 41 to 60 years. Other clinical features included apraxia, aphasia, and agnosia (Ancolio et al., 1999). The mutation was found in the affected proband and her affected uncle, but was absent from her unaffected mother.

This mutation was also found in one Korean individual with early onset Alzheimer's disease and a family history of dementia. Age of onset in this individual was 41 years, beginning with progressive memory and visuospatial impairment associated with apraxia, bradykinesia, and epilepsy (Park et al., 2008).

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

Neuropathology

Neuropathological data are unavailable. Progressive cortical atrophy was seen by MRI and hypometabolism by PET in one affected individual (Park et al., 2008).

Biological Effect

This mutation is unusual in that it was found to reduce total Aβ production. In HEK-293 cells, this mutation caused a significant reduction in Aβ40 with no change in Aβ42. There was a marked increase in N-terminally truncated Aβ42 (Aβx-42), but N-terminally truncated Aβ40 (Aβx-40) was not affected. An increase in secreted APPα was also observed (Ancolio et al., 1999). A subsequent study using NMR spectroscopy suggested V715M destabilizes the local helical conformation of the two APP ε-cleavage sites T48 and L49 (Chen et al., 2014). Because the destabilization is stronger at the T48 site, making it more accessible for cleavage than the L49 site, production of Aβ peptides was expected to shift towards the Aβ38 pathway, increasing Aβ42 levels. A comprehensive analysis of all Aβ peptides generated from V715M was consistent with this prediction, showing an increase in peptides from the Aβ38, but not the Aβ39, pathway (Devkota et al., 2021, Feb 2021 news). Also, this study showed mutation led to inefficient trimming of Aβ, resulting in increased levels of longer, membrane-anchored peptides that may be pathogenic.

Of note, a cryo-electron microscopy study of a fragment of APP bound to presenilin 1 suggests V715 is closely apposed to PSEN1's hydrophobic residue W165, one of PSEN1's sparse interactions with the lipid-exposed APP transmembrane helix (Zhou et al., 2019; Jan 2019 news). Moreover, a study using molecular dynamics simulations suggested V715 and I716 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).

The T714M 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. V715M: 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.

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. V715M: 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: 26 May 2023

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References

News Citations

Paper Citations

Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frébourg T, Checler F. Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24. PubMed.
Park HK, Na DL, Lee JH, Kim JW, Ki CS. Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease. J Korean Med Sci. 2008 Apr;23(2):213-7. PubMed.
Chen W, Gamache E, Rosenman DJ, Xie J, Lopez MM, Li YM, Wang C. Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site. Nat Commun. 2014;5:3037. 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 V715M (French)

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