Overview

Pathogenicity: Alzheimer's Disease : Benign, Dilated Cardiomyopathy : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PP2, PP3, BS1, BS2
Clinical Phenotype: Dilated Cardiomyopathy
Position: (GRCh38/hg38):Chr14:73211811 A>G
Position: (GRCh37/hg19):Chr14:73678519 A>G
dbSNP ID: rs121917809
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAT to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

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.

This variant 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). All of these 24 carriers were of African ancestry. Moreover, the variant was found in a Hispanic control participating of the Alzheimer’s Disease Sequencing Project (Lee et al., 2023, see suppl table 9).

Neuropathology
Unknown

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).

Pathogenicity

Alzheimer's Disease : Benign

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

PS3-P

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. D333G: Aβ42 production slightly reduced in vitro. Altered calcium signaling in fibroblasts.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

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

Last Updated: 16 Nov 2023

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References

Paper Citations

Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin RP, Jakobs PM, Litt M, Hershberger RE. 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.
Lee W-P, Choi SH, Shea MG, Cheng P-L, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, DeJager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang L-S, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project. 2023 Sep 02 10.1101/2023.09.01.23294953 (version 1) medRxiv.
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.
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.

Mutations

PSEN1 D333G

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