Mutations
PSEN1 L392P
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PM1, PM2, PM5, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683879 T>C
dbSNP ID: rs63750218
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: CTG to CCG
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 11
Findings
This mutation was found in an Italian man with a family history of AD with psychiatric symptoms (Tedde et al., 2000). In four family members, spanning three generations, disease onset was characterized by bipolar affective symptoms and mild memory loss occurring, on average, at 38 years of age. The mutation was present in the proband and absent from 50 unrelated subjects, as well as from the gnomAD variant database (gnomAD v2.1.1, August 2021).
Neuropathology
Neuropathological data are unavailable, but MRI revealed moderate atrophy of the temporal lobes in a symptomatic family member.
Biological Effect
The biological effect of this mutation is unknown, but a pathogenic mutation affecting the same residue, L392V, has been reported and several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). Moreover, L392 is in a domain that binds several proteins, including β-catenin and neuronal plakophilin-related armadillo protein/δ-catenin (Tedde et al., 2000).
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.
PM1-M
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
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: 22 Feb 2022
References
Mutations Citations
Paper Citations
- Tedde A, Forleo P, Nacmias B, Piccini C, Bracco L, Piacentini S, Sorbi S. A presenilin-1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset. Neurology. 2000 Nov 28;55(10):1590-1. PubMed.
- Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
External Citations
Further Reading
Learn More
Protein Diagram
Primary Papers
- Tedde A, Forleo P, Nacmias B, Piccini C, Bracco L, Piacentini S, Sorbi S. A presenilin-1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset. Neurology. 2000 Nov 28;55(10):1590-1. PubMed.
Other mutations at this position
Alzpedia
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