Mutations
PSEN1 M139R
Quick Links
Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PM2, PM5, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173643 T>G
Position: (GRCh37/hg19):Chr14:73640351 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: ATG to AGG
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 5
Findings
This variant was reported in a French individual from a large cohort of patients with autosomal dominant early onset Alzheimer’s disease (Zarea et al., 2016). Clinical details are unavailable, except that the carrier did not have seizures.
This variant was absent from the gnomAD variant database (v2.1.1, Feb 2022).
Neuropathology
Unknown.
Biological Effect
The biological effect of this variant is unknown, but multiple variants at this site have been reported to disrupt PSEN1 function and are classified as pathogenic. Moreover, the variant's PHRED-scaled CADD score, which integrates diverse information, was above 20, suggesting a damaging effect (CADD v.1.6, Sep 2021).
Of note, several variants at this position, including substitution of another basic amino acid, M139K, have been classified as pathogenic.
Pathogenicity
Alzheimer's Disease : Not Classified*
*This variant fulfilled some pathogenic ACMG-AMP criteria, and several variants at this position, including substitution to another basic amino acid, were classified as pathogenic. However, this variant 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.
PM5-M
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
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: 01 Apr 2022
References
Mutations Citations
Paper Citations
- Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
Further Reading
No Available Further Reading
Protein Diagram
Other mutations at this position
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