Mutations

PSEN1 R278S

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198095 A>C
Position: (GRCh37/hg19):Chr14:73664803 A>C
dbSNP ID: rs63750524
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGA to AGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a woman with a family history of dementia and spastic paraplegia (Raman et al., 2007). The proband developed progressive difficulties walking, poor balance, and slurred speech at age 39, and within a year, began experiencing memory impairment. By age 42, she had lower limb spasticity and weakness with bilateral Babinski signs, as well as upper extremity hyperreflexia. She also had impaired visual and verbal anterograde memory, and performed poorly on visuospatial tasks. Four additional affected family members, spanning three generations, had similar neurological presentations, and the family history was consistent with autosomal dominant inheritance. 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Unknown

Biological Effect
Although the biological effect of this mutation is unknown, other mutations at this site have been reported to impair γ-secretase activity. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that R278 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for APP cleavage (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).

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-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. R278S: 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: 28 Feb 2022

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References

News Citations

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

Paper Citations

  1. Raman A, Lin X, Suri M, Hewitt M, Constantinescu CS, Phillips MF. A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis. J Neurol Sci. 2007 Sep 15;260(1-2):78-82. PubMed.
  2. 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.
  3. 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. Raman A, Lin X, Suri M, Hewitt M, Constantinescu CS, Phillips MF. A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis. J Neurol Sci. 2007 Sep 15;260(1-2):78-82. PubMed.

Other mutations at this position

View Table

Alzpedia

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