Mutations

PSEN2 P123L

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073250 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a Chinese family affected by familial Alzheimer’s disease (Xia et al., 2015). The reported pedigree shows four affected individuals over four generations. In this family the disease presented as cognitive decline with parkinsonism and myoclonic jerks. The proband developed symptoms at age 57, staring with memory loss and personality changes, including irritability and apathy. She later developed rigidity in her hands and a persistent myoclonic jerking of her left hand. 

Of the 15 family members genotyped, seven were mutation carriers; however, only the proband met diagnostic criteria for AD. The other six mutation carriers were asymptomatic at the time of the report at ages 81, 58, 49, 53, 37, and 27 years. The mutation was absent from nine unaffected family members, 100 controls, and the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

Unknown. Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions.

Biological Effect

In a mouse neuroblastoma cell assay, this variant increased Aβ42 and decreased Aβ40 secretion, resulting in an approximately twofold increase in the Aβ42/Aβ40 ratio compared with that of cells expressing wildtype PSEN2 (Hsu et al., 2020).

This mutation was predicted to be probably damaging by in silico analysis (Xia et al., 2015, Hsu et al., 2020) 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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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.

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.

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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. Xia M, Chen S, Shi Y, Huang Y, Xu J, Zhao T, He S, Wu Y, Xu C, Zang W, Zhang J. Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. Neurobiol Aging. 2015 Dec;36(12):3334.e13-8. Epub 2015 Sep 8 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. Xia M, Chen S, Shi Y, Huang Y, Xu J, Zhao T, He S, Wu Y, Xu C, Zang W, Zhang J. Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. Neurobiol Aging. 2015 Dec;36(12):3334.e13-8. Epub 2015 Sep 8 PubMed.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.