Mutations

PSEN2 V139M

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS3, BP4
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr1:227073297 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a patient who experienced symptom onset at age 76 with the development of memory and language deficits. Disease progression was slow, but 10 years after symptom onset his speech was incomprehensible and he was unable to recognize his children. He received a diagnosis of late-onset Alzheimer's disease. There was a family history of dementia in the proband's father (death at age 80) and two sisters (death at age 79 and 83), but segregation could not be assessed. This mutation was not detected in 100 age-matched cognitively healthy controls, but pathogenicity could not be definitively established. The proband also carried a known polymorphism in PSEN1, E318G (Bernardi et al., 2008).

The frequency of this mutation in the gnomAD variant database was 0.0001062, including 30 heterozygotes of different ethnicities (gnomAD v2.1.1, Nov 2021).  

Neuropathology

The proband was reported to have bilateral hypoperfusion in the parietal-temporal lobes (Bernardi et al., 2008).

Biological Effect

In mouse neuroblastoma cells transfected with this variant, secreted Aβ42 and Aβ40 levels, as well as the Aβ42/Aβ40 ratio, were not significantly different from those observed in control cells transfected with wildtype PSEN2 (Hsu et al., 2020). V139 is not conserved in PSEN1 and the V139M variant had a PHRED-scaled CADD score (18.5) below 20, a commonly used threshold for predicting deleteriousness (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.  V139M: 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. Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Puccio G, Colao R, Frangipane F, Mirabelli M, Smirne N, Maletta RG, Bruni AC. Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008 Apr;255(4):604-6. Epub 2008 Mar 25 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.

Other Citations

  1. E318G

Further Reading

Papers

  1. Gallo M, Tomaino C, Bernardi L, Maletta R, Anfossi M, Geracitano S, Vasso F, Puccio G, Colao R, Frangipane G, Mirabelli M, Smirne N, Muraca MG, De Vito O, Bruni AC. PS1 polymporphism and a novel PS2 mutation in a patient with late-onset familial Alzheimer's disease. Alzheimers Dement. 2008;4(S2):T585

Protein Diagram

Primary Papers

  1. Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Puccio G, Colao R, Frangipane F, Mirabelli M, Smirne N, Maletta RG, Bruni AC. Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008 Apr;255(4):604-6. Epub 2008 Mar 25 PubMed.

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