Mutations

PSEN2 A23A

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PS4, BA1, BS1, BS2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226881976 T>C
Position: (GRCh37/hg19):Chr1:227069677 T>C
dbSNP ID: rs11405
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: GCT to GCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 4

Findings

This synonymous variant is very common worldwide with a high frequency (0.7576) in the gnomAD variant database (v2.1.1, Oct 2021), and a similar frequency in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death (Oct 2021).

A study of a small group of Japanese patients—288 AD patients, 6 patients with Lewy body dementia (LBD), and 105 controls—found no association between this variant and either AD or LBD (Suzuki et al., 2016).

The less frequent T allele was nominally associated with AD risk in a case-control study of 1154 AD patients and 2403 controls of Chinese ancestry (OR=0.88, 95% CI 0.80-0.98, p = 0.011 after adjusting for age, gender, and APOE4 status) (Xiao et al., 2022). The frequency of the allele was 0.55 in the patient group and 0.52 in the control group. In gnomAD, the frequency in East Asians was 0.55 (gnomAD v2.1.1, Jan 2023).

The variant has also been described, in heterozygous form, in four Turkish patients diagnosed with early onset Alzheimer’s disease (AD) together with another, very common synonymous variant, PSEN2 N43N (Eryilmaz et al., 2021). One of these carriers also had the PSEN1 mutation L364P. Age at onset ranged from 55 to 61 years of age. The N34N/A23A variant combination was also detected in a family with early onset AD. In this case, all members were A23A homozygotes with a mix of N34N homo- and heterozygotes. Several unaffected carriers were identified in this family, as well as in family members of one of the patients. Their ages were not reported.

Neuropathology
Neuropathology data are unavailable, but three of four carriers were reported to have atrophy assessed by MRI that was consistent with AD. The carrier with no detectable AD-relevant atrophy was the youngest, aged 55 years (Eryilmaz et al., 2021).

Biological Effect
The biological effect of this variant is unknown but its PHRED-scaled CADD score, which integrates diverse information in silico, was very low (5.75),  suggesting it does not have a damaging effect (CADD v.1.6, Oct 2021). Eryilmaz and colleagues hypothesized that together with N43N, A23A may contribute to early onset AD (Eryilmaz et al., 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.

PS4-S

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

BA1

Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database. A23A: This variant was found in about 75% of individuals worldwide.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

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. A23A: Found in about 75% of individuals in the Healthy Exomes (HEX) database.

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: 11 Apr 2023

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References

Mutations Citations

  1. PSEN2 N43N
  2. PSEN1 L364P

Paper Citations

  1. Suzuki A, Shibata N, Kasanuki K, Nagata T, Shinagawa S, Kobayashi N, Ohnuma T, Takeshita Y, Kawai E, Takayama T, Nishioka K, Motoi Y, Hattori N, Nakayama K, Yamada H, Arai H. Genetic Association between Presenilin 2 Polymorphisms and Alzheimer's Disease and Dementia of Lewy Body Type in a Japanese Population. Dement Geriatr Cogn Dis Extra. 2016;6(1):90-7. Epub 2016 Mar 16 PubMed.
  2. Xiao X, Liu H, Zhou L, Liu X, Xu T, Zhu Y, Yang Q, Hao X, Liu Y, Zhang W, Zhou Y, Wang J, Li J, Jiao B, Shen L, Liao X. The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population. CNS Neurosci Ther. 2023 Jan;29(1):122-128. Epub 2022 Oct 10 PubMed.
  3. Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.

Other Citations

  1. HEX

Further Reading

Papers

  1. Suzuki A, Shibata N, Kasanuki K, Nagata T, Shinagawa S, Kobayashi N, Ohnuma T, Takeshita Y, Kawai E, Takayama T, Nishioka K, Motoi Y, Hattori N, Nakayama K, Yamada H, Arai H. Genetic Association between Presenilin 2 Polymorphisms and Alzheimer's Disease and Dementia of Lewy Body Type in a Japanese Population. Dement Geriatr Cogn Dis Extra. 2016;6(1):90-7. Epub 2016 Mar 16 PubMed.

Protein Diagram

Primary Papers

  1. Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.

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