Mutations

PSEN2 M298T

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS4, PP1, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226891284 T>C
Position: (GRCh37/hg19):Chr1:227078985 T>C
dbSNP ID: rs1482790603
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. M298T: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. M298T: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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References

Paper Citations

  1. Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T. 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. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. 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. Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T. 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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