Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3, BS3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27328042 A>C
dbSNP ID: rs201384815
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to CAG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 12

Findings

This variant was one of several rare polymorphisms detected by exome sequencing in a British cohort composed of 47 unrelated early onset Alzheimer’s cases and 179 elderly controls free of AD pathology. The mutation was detected in one Caucasian individual who had been diagnosed with AD at or before the age of 65, although a more precise age at onset was not available. The mutation was not found in any of the controls screened (Sassi et al., 2014).

Four heterozygous carriers of this variant were found in the gnomAD database (version 2.1.1, Oct 2021), all from the European (non-Finnish) population.

Neuropathology

One reported carrier of this variant had autopsy-confirmed AD. Further details have not been reported (Sassi et al., 2014).

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and slightly greater amounts of Aβ40 compared with cells expressing wild-type APP. The Aβ42/Aβ40 ratio was not significantly different from controls (Hsu et al., 2020). In silico, however, this variant was predicted to be deleterious with a PHRED-scaled CADD score greater than 20 (CADD v1.6, Mar 2022). Sassi and colleagues considered it most likely a rare, benign polymorphism in APP because it occurs outside of exons 16 and 17, in which all of the pathogenic mutations known at that time were located (Sassi et al., 2014).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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.

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

Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Mann D, Snowden J, Neary D, Harris J, Bras J, ARUK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 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 K496Q

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