Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PM1, PP2, PP3, BS1, BS2, BS3
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr21:27264107 C>T
dbSNP ID: rs1800557
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant was originally described in an individual with schizophrenia and cognitive deficits (Jones et al., 1992), raising the possibility of pathogenicity. Subsequent studies did not support a pathogenic role for this variant in either schizophrenia or Alzheimer's disease. The variant was not associated with schizophrenia in a study of 191 individuals in 24 families (Mant et al., 1992), and in a study of 98 AD cases and 56 elderly healthy controls, it was found only in a control (Forsell et al., 1995). The variant has been reported in eight individuals of European ancestry, with a global frequency of 0.00006592 in the ExAC variant database (ExAc v1.0, Sep 2020).

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted less than half the amount of both Aβ42 and Aβ40 compared with cells expressing wild-type APP. The Aβ42/Aβ40 ratio was similar to controls (Hsu et al., 2020). In silico analyses predicted this mutation is probably damaging (PolyPhen) and deleterious (SIFT). Hsu et al. classified the mutation as not pathogenic and possibly protective.

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. A713V: Most carriers are of European descent.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 11 Mar 2022

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References

Paper Citations

Jones CT, Morris S, Yates CM, Moffoot A, Sharpe C, Brock DJ, St Clair D. Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia. Nat Genet. 1992 Jul;1(4):306-9. PubMed.
Mant R, Asherson P, Gill M, McGuffin P, Owen M, Wert SE, Gregory RJ, Smith AE, Cohn JA, Wilson JM. Schizophrenia scepticism. Nat Genet. 1992 Sep;2(1):12. PubMed.
Forsell C, Lannfelt L. Amyloid precursor protein mutation at codon 713 (Ala-->Val) does not cause schizophrenia: non-pathogenic variant found at codon 705 (silent). Neurosci Lett. 1995 Jan 23;184(2):90-3. PubMed.
Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Mutations

APP A713V

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