Mutations

PSEN1 L364P

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73678612 T>C
dbSNP ID: rs966909396
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was identified in a Turkish woman diagnosed with early onset Alzheimer’s disease (Eryilmaz et al., 2021). She had no known family history of the disease. Her age of onset was 61 and she was described as having moderate to severe cognitive impairment. The mutation was found by heteroduplex analysis using DNA from 20 healthy controls, followed by sequence analysis of four AD-relevant genes, including PSEN1. Of note, two synonymous substitutions in PSEN2 were also identified in this carrier: A23A and N43N.

Global frequency in gnomAD was 0.000003977, with a single allele count in the Latino/Admixed American category (gnomAD v2.1.1, April 2021).

Neuropathology
Neuropathology data are unavailable, but an MRI scan was reported as showing atrophy consistent with AD (Eryilmaz et al., 2021).

Biological Effect
The biological effect of this variant is unknown. Although some in silico algorithms predicted structural and functional alterations, others classified it as likely benign (Eryilmaz et al., 2021). The CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 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.

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

Mutations Citations

  1. PSEN2 A23A
  2. PSEN2 N43N

Paper Citations

  1. Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.

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