Pathogenicity: Dilated Cardiomyopathy : Not Classified, Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Dilated Cardiomyopathy
Reference Assembly: GRCh37/hg19
Position: Chr14:73678519 A>G
dbSNP ID: rs121917809
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAT to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10


This mutation was identified in a screen of the PSEN1 and PSEN2 genes of 132 families with familial dilated cardiomyopathy (Li et al., 2006). The African American family carrying this mutation had six affected members with aggressive heart disease emerging between 24 and 69 years of age. One mutation carrier was diagnosed with Alzheimer's disease dementia at age 71, but no autopsy was performed. Three members with heart disease who were tested for the mutation were found to be carriers, while six unaffected members tested negative. The mutation was absent from 413 unrelated and unaffected controls, but it was present at a frequency of 0.0001025 with an allele count of 29 in the gnomAD variant database (gnomAD v2.1.1, July 2021) and at a frequency of 0.0001046 with an allele count of 24 in the subdivision of the database that excludes data from neurological studies (gnomAD v2.1.1 (non-neuro), July 2021).


Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a moderate reduction in Aβ42 production with little or no effect on the Aβ42/Aβ40 ratio (Sun et al., 2017). However, it may affect intracellular calcium dynamics as suggested by the observation of altered calcium signaling in cultured skin fibroblasts (Li et al., 2006).

Although in silico algorithms to predict the effects of this variant on protein function yielded conflicting results in one report (Xiao et al., 2021), the D333G substitution results in a nonconservative substitution in a highly conserved position (Li et al., 2006), and the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Last Updated: 07 Oct 2021


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Paper Citations

  1. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.
  2. . 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.
  3. . 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 v2.1.1
  2. gnomAD v2.1.1 (non-neuro)
  3. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.


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