Mutations

PSEN2 F183S

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227075841 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTC to TCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7

Findings

This variant was found in a 46-year-old woman in a cohort of individuals with onset of clinical probable Alzheimer’s disease (AD) before age 70 at the Mayo Clinic in Jacksonville, Florida (Wojtas et al., 2012). Members of the cohort were screened for mutations in genes associated with AD and frontotemporal dementia (exon 16 and 17 of APP, exons 3-12 of PSEN1, and exons 3-12 of PSEN2).

The carrier’s first clinical symptom, reported at age 46, was memory loss. Her family history was unknown, as she was adopted. She had an APOE3/3 genotype.

This variant is absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology
Neuropathological data for this mutation are unavailable.

Biological Effect
The biological effect of this mutation is unknown, but it is evolutionarily conserved and its homolog in PSEN1, F177S, is pathogenic. Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). Wojtas and colleagues considered that, taken together, their observations provided support for F183S also being pathogenic (Wojtas et al., 2012).

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.

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.

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

Mutations Citations

  1. PSEN1 F177S

Paper Citations

  1. Wojtas A, Heggeli KA, Finch N, Baker M, Dejesus-Hernandez M, Younkin SG, Dickson DW, Graff-Radford NR, Rademakers R. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Wojtas A, Heggeli KA, Finch N, Baker M, Dejesus-Hernandez M, Younkin SG, Dickson DW, Graff-Radford NR, Rademakers R. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16 PubMed.

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