Mutations

PSEN2 I146T

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073319 T>C
dbSNP ID: rs1215971988
Coding/Non-Coding: Coding
Mutation Type:
Codon Change: ATC to ACC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This variant was found in two Chinese women with Alzheimer's disease. One was a Han Chinese patient with no known family history of the disorder (Mao et al., 2021). Her age at onset was 70 years. The other, who did have a family history of disease, presented with memory loss at age 59 and developed depression and other psychiatric symptoms in subsequent years (Sun et al., 2021). Her diagnosis was AD/frontotemporal dementia. Both carriers had APOE3/E4 genotypes.

A single East Asian heterozygote carrying this mutation was reported in the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology
Unknown.

Biological Effect
In silico algorithms (SIFT, Polyphen, Mutation Taster, M-CAP, and LRT) predicted a damaging or possibly damaging effect for this variant (Mao et al., 2021, Sun et al., 2021) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above the commonly used deleteriousness threshold of 20 (CADD v.1.6, Oct 2021). Both Mao et al., and Sun et al. classified this as a variant of uncertain significance using the ACMG guidelines (Richards et al., 2015).

Last Updated: 04 Nov 2021

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References

Paper Citations

  1. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
  2. . Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing. Front Aging Neurosci. 2021;13:745407. Epub 2021 Oct 14 PubMed.
  3. . 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. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.

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