Mutations

PSEN1 L248R

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):Chr14:73192838 T>G
Position: (GRCh37/hg19):Chr14:73659546 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a man who presented with AD symptoms at age 54, with no known family history of the disease (Clarimón et al., 2008, Guerreiro et al., 2010). It was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Although neuropathology findings are unavailable, the patient showed atrophy in the lateral fissure and, to a lesser extent, in parietofrontal regions as assessed by neuroimaging.

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed decreased production of all Aβ peptides, with a slight increase in the Aβ42/Aβ40 ratio and decreased Aβ37/Aβ42 ratio, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. In vitro studies using APP C99 as a substrate also showed the mutation increased the Aβ42/Aβ40 ratio and decreased poduction Aβ40 and Aβ42 (Bai et al., 2015; Sun et al., 2017). 

Computer modeling of the structure of the mutant protein predicted the substitution would block the substrate's access to PSEN1's active site (Soto-Ospina et al., 2021). Moreover, 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).

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. L248R: Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, but production of all Aβ 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: 08 Dec 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, Boada M, Bullido MJ, Ferrer I, Martínez-Lage P, Masdeu J, Molina L, Molinuevo JL, Pastor P, Pérez-Tur J, Rey MJ, Sánchez-Valle R, Tàrraga L, Valdivieso F, Singleton A, Hardy J. Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. 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.
  3. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  4. Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  5. 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.
  6. Soto-Ospina A, Araque Marín P, Bedoya G, Sepulveda-Falla D, Villegas Lanau A. Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer's Disease on the Orthosteric Site. Front Mol Biosci. 2021;8:649990. Epub 2021 Jun 2 PubMed.
  7. 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

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, Boada M, Bullido MJ, Ferrer I, Martínez-Lage P, Masdeu J, Molina L, Molinuevo JL, Pastor P, Pérez-Tur J, Rey MJ, Sánchez-Valle R, Tàrraga L, Valdivieso F, Singleton A, Hardy J. Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. 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.

Other mutations at this position

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