Mutations

PSEN1 S230R

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659493 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGT to AGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated early onset Alzheimer’s disease cases and 179 elderly controls who were free of AD neuropathology. The S230R mutation was detected in one Caucasian individual who had been diagnosed with AD at the age of 58, following a two-year history of memory problems. Initially, other cognitive domains were intact, and the patient had insight into his condition. His symptoms worsened over time and he developed difficulties with verbal expression and visuospatial tasks. He later developed severe parkinsonian symptoms and myoclonus, and eventually became mute. He died at age 66, 10 years after symptom onset. The patient’s father died in his early 60s of a similar dementing illness, but further clinical details were not available (Sassi et al., 2014).

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

Neuropathology

SPECT imaging early in the disease showed hypoperfusion in the left posterior lobe. A later SPECT scan showed bilateral parietal hypoperfusion, still more marked on the left side. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaque and tangle pathology (CERAD C, Braak VI).

Biological Effect

Unknown.  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 (Sassi et al., 2014Xiao et al., 2021), and has probable pathogenicity according to the algorithm proposed by Guerreiro et al., 2010.

Last Updated: 10 Sep 2021

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References

Paper Citations

  1. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
  2. . 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.
  3. . 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

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.

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