Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226883808 A>G
Position: (GRCh37/hg19):Chr1:227071509 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAA to AGA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Chinese woman affected by early onset Alzheimer’s disease (Shi et al., 2015). She developed memory loss at age 53 and met clinical criteria for probable AD. Other symptoms included depression and language disturbances, including slow speech and word-finding difficulties. Her APOE genotype was E3/E3. Her family history was unknown.

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

Neuropathology

Nueropathological data are unavailable, but neuroimaging in one case showed diffuse cortical atrophy, especially in the posterior region and mild hippocampal atrophy (Shi et al., 2015). FDG-PET showed hypometabolism in the bilateral temporal, parietal, and occipital regions, as well as other areas. PIB-PET showed amyloid deposition in the frontal lobe, lateral temporal lobe, parietal lobe, posterior cingulate cortex, precuneus, and striatum.

Biological Effect

This variant does not appear to alter the ratio of Aβ42/Aβ40. A cellular assay using mouse neuroblastoma cells expressing the mutant protein showed secretion of similar amounts of Aβ42 and Aβ40 as cells expressing wild-type PSEN2 (Hsu et al., 2020).

The variant is conserved between PSEN2 and PSEN1, and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

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.

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.

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: 22 Feb 2022

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References

Paper Citations

Shi Z, Wang Y, Liu S, Liu M, Liu S, Zhou Y, Wang J, Cai L, Huo YR, Gao S, Ji Y. Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 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

PSEN2 K82R

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