Mutations

PSEN1 G378R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype:
Reference Assembly: GRCh37 (105)
Position: Chr14:73683836 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to CGA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This variant was identified in a genetic screen of 103 Spanish patients with early onset Alzheimer’s disease (AD) or fronto-temporal dementia (Ramos-Campoy et al., 2020). Whole-exome sequencing revealed the variant in a 50-year-old Spanish woman with dementia who had been suffering from episodic memory lapses, diminished language fluency, and word-finding difficulties for four years. Her APOE genotype was E3/E3. Of note, her mother’s cognition began declining at age 50, and that of her maternal uncle at age 58. The mutation was absent from the gnomAD variant database.

Neuropathology
Neuropathological data are unavailable, but a brain MRI of the proband revealed bilateral, fronto-temporo-parietal atrophy. Measurements of cerebrospinal fluid biomarkers were consistent with AD.

Biological Effect
The biological effects of this variant are unknown, but several in silico algorithms predicted the substitution to be deleterious, including SIFT, Polyphen-2, LRT, Mutation Taster, Mutation Assessor, FATHMM, LR, and Radial SVM. In addition, two pathogenic mutations, G378E and G378V, have been reported at the G378 position. Following the ACMG guidelines (Richards et al., 2015), Ramos-Campoy and colleagues classified the G378R variant as likely pathogenic (Ramos-Campoy et al., 2020).

Last Updated: 04 Nov 2020

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References

Mutations Citations

  1. PSEN1 G378E
  2. PSEN1 G378V

Paper Citations

  1. . Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.
  2. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.

Other mutations at this position

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