Mutations

PSEN2 P69A

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS3, BP4
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227071469 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCC to GCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Serbian patient who developed Alzheimer's disease at the age of 74. The proband's sister developed similar symptoms at age 76 and died at the age of 83. Segregation could not be assessed, but the authors note that P69A is likely to be a benign polymorphism based on its location in the protein (Dobricic et al., 2012).

This variant was reported in the gnomAD variant database at a frequency of 0.00008845 and an allele count of 25 (gnomAD v2.1.1, Nov 2021). All carriers were heterozygotes, most of European ancestry.

Neuropathology

Unknown.

Biological Effect

Compared with cells expressing wild-type PSEN2, mouse neuroblastoma cells expressing this variant secreted similar amounts of both Aβ42 and Aβ40, resulting in a similar Aβ42/Aβ40 ratio (Hsu et al., 2020). Although this variant is predicted to alter a residue in the N-terminal of PSEN2 that is conserved in PSEN1 (P47), its PHRED-scaled CADD score of 15.3 did not reach the threshold of 20 often used to predict deleteriousness in silico (CADD v.1.6, Nov 2021).

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  P69A: Most carriers were of European ancestry.

BS3-S

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

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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: 22 Feb 2022

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References

Paper Citations

  1. Dobricic V, Stefanova E, Jankovic M, Gurunlian N, Novakovic I, Hardy J, Kostic V, Guerreiro R. Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort. Neurobiol Aging. 2012 Jul;33(7):1481.e7-12. Epub 2012 Jan 4 PubMed.
  2. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Dobricic V, Stefanova E, Jankovic M, Gurunlian N, Novakovic I, Hardy J, Kostic V, Guerreiro R. Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort. Neurobiol Aging. 2012 Jul;33(7):1481.e7-12. Epub 2012 Jan 4 PubMed.

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