Mutations

PSEN2 M298T

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227078985 T>C
dbSNP ID: rs1482790603
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ACG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 10

Findings

This variant has been identified in several Chinese individuals with Alzheimer’s disease (AD). It was first reported in a Han Chinese patient diagnosed with probable AD according to the NINCDS-ADRDA and DSM-IV criteria (Wang et al., 2019).  This individual did not have a family history of AD and was APOE4 negative. Age at onset was 56 years.

A subsequent report described a family of the Chinese Familial Alzheimer’s Disease Network in which six family members across two generations were diagnosed with Alzheimer’s disease (Jia et al., 2020). Four members were genotyped and three were found to carry the mutation: two AD patients with ages at onset of 58 and 59 years, and one individual suffering from mild cognitive impairment at age 57. The single non-carrier was cognitively healthy at age 65, suggesting cosegregation of the mutation with disease. All carriers were homozygous for the APOE3 allele.

The mutation was also found in a Han Chinese woman with AD and a family history of dementia (Mao et al., 2021). Her age at onset was 56 years. Her APOE genotype was APOE3/E4.

Three heterozygotes of East Asian ancestry are reported in the gnomAD variant database (v2.1.1, Oct 2021). The allele frequency in this population is 0.0001632 with a global frequency of 0.00001198.

Neuropathology
Unknown.

Biological Effect
The biological effect of this variant is unknown. Multiple in silico algorithms predicted a damaging effect, although not all (Wang et al., 2019, Jia et al., 2020, Mao et al., 2021). Its PHRED-scaled CADD score, which integrates diverse information in silico, was above the commonly used deleteriousness threshold of 20 (Wang et al., 2019).

Last Updated: 27 Oct 2021

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References

Paper Citations

  1. . Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.

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