Mutations

PSEN2 T18M

Overview

Pathogenicity: Alzheimer's Disease : Benign, Parkinson's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, MSA-P
Position: (GRCh38/hg38):Chr1:226881960 C>T
Position: (GRCh37/hg19):Chr1:227069661 C>T
dbSNP ID: rs143061887
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 4

Findings

This variant was first identified in a German subject of European ancestry who developed symptoms of Parkinson’s disease at age 62 (Blauwendraat et al., 2015). He presented with typical PD without atypical features or symptoms of AD until at least age 70. No family history of PD was reported.

T18M was also reported in a preprint that analyzed data from the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 13,825 late-onset AD cases and 14,715 controls. The variant was identified in one AD case and four controls (Wang et al., 2023, suppl table e-5).

Fifty-six heterozygotes were reported in the gnomAD variant database resulting in a global frequency of 0.000035 (v4.0.0, Feb 2024). Although most carriers (50) were of European ancestry, the allele frequency was highest in individuals of African ancestry (0.000067).

Neuropathology

Neuropathological data are unavailable.

Biological Effect

The biological effect of this mutation is unknown. It is predicted to be damaging in silico (Hsu et al., 2020), with a PHRED-scaled CADD score of 25.4 (v.1.6, Oct 2021), but it is not conserved between PSEN1 and PSEN2.

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.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  T18M: Most carriers were of European ancestry, but allele frequency was higher in individuals of African ancestry.

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: 13 Feb 2024

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References

Paper Citations

  1. Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016 Jan;37:208.e11-7. Epub 2015 Sep 30 PubMed.
  2. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
  3. 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. Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016 Jan;37:208.e11-7. Epub 2015 Sep 30 PubMed.

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