Mutations

APP E246K

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27394285 G>A
dbSNP ID: rs147485129
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 6

Findings

This variant was detected in an individual with apparently sporadic AD (Frigerio et al., 2015).  There was no family history of dementia.  Other than a diagnosis of AD, clinical details related to this individual were not reported.

The variant is found in the gnomAD variant database, including five alleles, three found in heterozygotes of African descent, one in a South Asian individual, and one in a European individual (gnomAD v2.1.1, Oct 2021).

Neuropathology

Unknown.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and Aβ40 compared with cells expressing wild-type APP, resulting in a similar Aβ42/Aβ40 ratio (Hsu et al., 2020). In silico, the E246K variant was predicted to be possibly damaging by PolyPhen2 (Frigerio et al., 2015). The PHRED-scaled CADD score was above 20, suggesting a deleterious effect (CADD v.1.6, Sep 2021). Hsu and colleagues classifed this variant as a risk factor (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Likely Benign*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

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

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-P

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  E246K: Five carriers in gnomAD, three of African descent.

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: 15 Mar 2022

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References

Paper Citations

  1. 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.

Other Citations

  1. Frigerio et al., 2015

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

Alzpedia

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