Mutations

PSEN1 A136G

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173634 C>G
Position: (GRCh37/hg19):Chr14:73640342 C>G
dbSNP ID: rs41345849
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in an analysis of 130 members of a Chinese family (Xu et al., 2002). The search, which focused on PSEN1 exons 4 and 5, identified the mutation in nine individuals, five of whom had been diagnosed with Alzheimer's disease and four of whom were asymptomatic. The mutation was absent from other family members, as well as from 50 controls, and the gnomAD variant database (gnomAD v.2.1.1, May 2021).

Biological Effect

Neuroblastoma cells carrying the mutation showed enhanced sensitivity to trophic withdrawal (Fang and Jia, 2007, Fang and Jia, 2008). In vitro assays showed a moderate decrease in both Aβ40 and Aβ42 production, with the Aβ42/Aβ40 ratio remaining roughly similar to wild-type (Sun et al., 2017). Moreover, the mutation has been reported to enhance PSEN1 cleavage of STIM1, a calcium sensor in the endoplasmic reticulum that promotes the replenishment of the cation when stores run low (Tong et al., 2016, see also Sep 2016 news). The enhanced cleavage causes calcium influx to drop, which appears to disrupt dendritic spines. 

Although some in silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) yielded conflicting results (Fang and Jia, 2007, Fang and Jia, 2008, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because it was found in a single affected family without evidence of cosegregation or a functional effect clearly tied to AD, and it is absent, or very rare, in the gnomAD database.

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

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. A136G: The Aβ42/Aβ40 ratio was minimally affected; other cellular functions were disrupted.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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

News Citations

  1. Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor

Paper Citations

  1. Xu E, Jia J, Sun W. [Mutation site of presenilin-1 gene in familial Alzheimer's disease]. Zhonghua Yi Xue Za Zhi. 2002 Nov 25;82(22):1518-20. PubMed.
  2. Fang BY, Jia JP. [The effect of two newly Chinese presenilin-1 mutations on the sensitivity to trophic factor withdrawal in human neuroblastoma cells]. Zhonghua Yi Xue Za Zhi. 2007 Jan 30;87(5):336-40. PubMed.
  3. Fang BY, Jia JP. Human neuroblastoma cells transfected with two Chinese presenilin 1 mutations are sensitized to trophic factor withdrawal and protected by insulin-like growth factor-1. Chin Med J (Engl). 2008 May 20;121(10):910-5. PubMed.
  4. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  5. Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal. 2016 Sep 6;9(444):ra89. PubMed.
  6. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v.2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Xu E, Jia J, Sun W. [Mutation site of presenilin-1 gene in familial Alzheimer's disease]. Zhonghua Yi Xue Za Zhi. 2002 Nov 25;82(22):1518-20. PubMed.

Other mutations at this position

View Table

Alzpedia

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