Mutations

PSEN1 R157S

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640406 G>T
dbSNP ID: rs201617677
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGG to AGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant was found using whole-exome sequencing to screen 15 patients from Chinese families with familial AD (Jiang et al., 2019). The proband was 60 years old at disease onset. His initial symptom was memory loss which progressed slowly, with irritability developing two years later. His mother died at approximately 90 years of age with cognitive impairment. The variant was also reported in a Han Chinese man in Taiwan with depression and amnesic onset at age 51 (Lin et al., 2020). Family history was unavailable.

The variant was found in three population-based variant databases: the 1000 Genomes Project (0.0002), ExAC (0.0000659), and gnomAD (0.0000609), as well as in the East Asian subpopulation in ExAC (0.00009244) and Taiwan View (0.00033) (Jiang et al., 2019; Lin et al., 2020).

Neuropathology
Neuropathological data are unavailable, but at age 59, the patient in Taiwan had posterior cortical atrophy and mild medial temporal atrophy, as assessed by MRI (Lin et al., 2020).

Biological Effect
In silico analyses predict the mutation is likely pathogenic. Polyphen 2 predicted it to be probably damaging and SIFT classified it as deleterious. The mutation’s CADD score was 31. Both Jiang et al. and Lin et al. classified this variant as of uncertain significance (Jiang et al., 2019; Lin et al., 2020).

Last Updated: 17 Nov 2020

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References

Paper Citations

  1. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  2. . Mutational analysis in familial Alzheimer's disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile. Sci Rep. 2020 Nov 13;10(1):19769. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.

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