Mutations
PSEN1 L235R
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192799 T>G
Position: (GRCh37/hg19):Chr14:73659507 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: CTG to CGG
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 7
Findings
This presenilin-1 mutation was detected in a Spanish woman diagnosed with early onset Alzheimer’s disease. She first developed episodic memory impairment at the age of 47, along with reduced language fluency and word-finding difficulties. Behavioral changes, notably apathy and self-neglect, also appeared early. Gait disturbance, pyramidal signs, and myoclonus were absent. The reported pedigree indicates eight individuals over two generations affected by early onset dementia in a pattern consistent with autosomal-dominant inheritance, although a lack of samples precluded segregation analysis. Clinical information was limited for affected family members, but the mean age of onset was reported as 45 years (range: 41 to 60 years) and the disease course was noted to be rapid. PSEN2 and APP were not screened (Antonell et al., 2011).
This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).
Neuropathology
Unknown. MRI showed bilateral atrophy, especially within the parietal and temporal lobes. Analysis of the cerebral spinal fluid showed low levels of Aβ42 and elevated total tau and phospho-tau 181 (Antonell et al., 2011).
Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it abrogates Aβ40 production and drastically reduces Aβ42 production (Sun et al., 2017). Also, the mutation caused incomplete endoproteolytic processing of PSEN1. 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). It is classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Antonell et al., 2011).
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.
PS3-M
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. L235R: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.
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
Paper Citations
- Antonell A, Balasa M, Oliva R, Lladó A, Bosch B, Fabregat N, Fortea J, Molinuevo JL, Sánchez-Valle R. A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease. Neurosci Lett. 2011 May 27;496(1):40-2. PubMed.
- Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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.
- Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
External Citations
Further Reading
Protein Diagram
Primary Papers
- Antonell A, Balasa M, Oliva R, Lladó A, Bosch B, Fabregat N, Fortea J, Molinuevo JL, Sánchez-Valle R. A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease. Neurosci Lett. 2011 May 27;496(1):40-2. PubMed.
Other mutations at this position
Alzpedia
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