Mutations

PSEN1 C263R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198048 T>C
Position: (GRCh37/hg19):Chr14:73664756 T>C
dbSNP ID: rs63750543
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in an individual with autopsy-confirmed AD and a family history of the disease (Wasco et al., 1995). Age of onset was approximately 47 years, with an average of 50 years for all four affected family members who also carried the mutation. The mutation was absent from affected members of 29 families with early onset AD and 12 families with late-onset AD, as well as from 106 controls. It was also absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathology of the proband was consistent with AD.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased production of both Aβ40 and Aβ42, and an approximately two-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

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). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Pathogenicity

Alzheimer's Disease : Pathogenic

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. C263R: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. C263R: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Wasco W, Pettingell WP, Jondro PD, Schmidt SD, Gurubhagavatula S, Rodes L, DiBlasi T, Romano DM, Guenette SY, Kovacs DM. Familial Alzheimer's chromosome 14 mutations. Nat Med. 1995 Sep;1(9):848. PubMed.
  2. 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.
  3. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. 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.
  5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. Leroy K, Boutajangout A, Richardson J, Octave JN, Lovestone S, Anderton BH, Brion JP. Mutant presenilin 1 proteins induce cell death and reduce tau-dependent processes outgrowth. Neurosci Lett. 2003 Dec 26;353(3):226-30. PubMed.

Protein Diagram

Primary Papers

  1. Wasco W, Pettingell WP, Jondro PD, Schmidt SD, Gurubhagavatula S, Rodes L, DiBlasi T, Romano DM, Guenette SY, Kovacs DM. Familial Alzheimer's chromosome 14 mutations. Nat Med. 1995 Sep;1(9):848. PubMed.

Other mutations at this position

View Table

Alzpedia

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