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):Chr21:25891783 T>G
Position: (GRCh37/hg19):Chr21:27264095 T>G
dbSNP ID: rs63749964
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to GGC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was reported in a three-generation family. As described, the "F19" pedigree had 10 affected individuals who met the NINCDS-ADRDA criteria for probable AD. The diagnosis was confirmed by autopsy in at least one family member. The average age of onset in this family was 59 ± 4 years (Chartier-Harlin et al., 1991). Additional screening of the APP gene in this family did not reveal any additional sequence abnormalities, supporting the pathogenicity of V717G. Moreover, the mutation was found in three affected carriers and was absent from 10 unaffected members indicating cosegregation with disease (Fidani et al., 1992).

This mutation was later identified in a woman from the United Kingdom considered to be affected by sporadic early onset AD. She met clinical criteria for probable AD, with onset at age 61. Additional clinical details were not reported (Barber et al., 2015).

In addition, the variant was found in an individual diagnosed with mild cognitive impairment (MCI) whose diagnosis and MMSE scores remained stable from ages 48 to 51 (Küçükali et al., 2022). The patient was part of a European multicenter cohort, the EMIF-AD MBD study.

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

Neuropathology

Neuropathology consistent with AD was seen at autopsy in at least one mutation carrier (Chartier-Harlin et al., 1991). Moreover, the levels of cerebrospinal fluid biomarkers, including Aβ42, phospho-tau181, and total tau, were within the AD range in the carrier with MCI (Küçükali et al., 2022).

Biological Effect

This mutation increases the Aβ42/Aβ40 ratio by increasing Aβ42 and decreasing Aβ40 (Tamaoka et al., 1994). A subsequent, more extensive survey of the Aβ peptides produced from this variant showed that the substitution increases total Aβ, Aβ48, Aβ46, Aβ45, Aβ42, and Aβ38 levels (Devkota et al., 2021, Feb 2021 news). Epsilon-cleavage was increased and shifted towards Aβ48. Moreover, in contrast to other APP pathogenic mutations, V717G facilitated ε-cleavage at a novel site resulting in production of, not only the standard ε-cleavage products Aβ48 and Aβ49, but Aβ46. The latter peptide was trimmed inefficiently, increasing the levels of long, membrane-anchored peptides that may be pathogenic.

A cryo-electron microscopy study of an APP fragment bound to PSEN1 revealed that V717 is nestled in a shallow hydrophobic pocket formed by PSEN1 F237, I387, and F388 (Zhou et al., 2019; Jan 2019).

V717G'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. V717G: 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-S

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. V717G: At least one family with >=3 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: 10 Nov 2023

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References

News Citations

Paper Citations

Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844-6. PubMed.
Fidani L, Rooke K, Chartier-Harlin MC, Hughes D, Tanzi R, Mullan M, Roques P, Rossor M, Hardy J, Goate A. Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val-->Ile. Hum Mol Genet. 1992 Jun;1(3):165-8. PubMed.
Barber IS, García-Cárdenas JM, Sakdapanichkul C, Deacon C, Zapata Erazo G, Guerreiro R, Bras J, Hernandez D, Singleton A, Guetta-Baranes T, Braae A, Clement N, Patel T, Brookes K, Medway C, Chappell S, Mann DM, ARUK Consortium, Morgan K. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease. Neurobiol Aging. 2016 Mar;39:220.e1-7. Epub 2015 Dec 29 PubMed.
Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJ, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Alzheimer's Disease Neuroimaging Initiative (ADNI), Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, Sleegers K, EMIF-AD Study Group. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimers Dement. 2023 Jun;19(6):2317-2331. Epub 2022 Dec 4 PubMed.
Tamaoka A, Odaka A, Ishibashi Y, Usami M, Sahara N, Suzuki N, Nukina N, Mizusawa H, Shoji S, Kanazawa I. APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1-42/43 and a beta 1-40) in familial Alzheimer's disease brain. J Biol Chem. 1994 Dec 30;269(52):32721-4. 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 V717G

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