Mutations

PSEN1 P218L

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192748 C>T
Position: (GRCh37/hg19):Chr14:73659456 C>T
dbSNP ID: rs140064975
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was found in a 55-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 symptoms were memory impairment and vision loss. She had a family history of dementia, including one relative with AD or memory problems. Her APOE genotype was APOE3/3.

This variant was found at a frequency of 0.000007952 in the gnomAD variant database with a count of two alleles (gnomAD v2.1.1, May 2021). It was absent from 641 healthy controls in the original study.

Neuropathology
Neuropathological data were not reported for this variant.

Biological Effect
The biological effect of this mutation is unknown, but in silico analyses predict this variant is probably damaging (Polyphen) and deleterious (SIFT) (gnomAD v2.1.1 (non-neuro), May 2021). P218 is highly evolutionarily conserved.

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.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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

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.

External Citations

  1. gnomAD v2.1.
  2. 1

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.

Other mutations at this position

View Table

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