Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192735 C>G
Position: (GRCh37/hg19):Chr14:73659443 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to GAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a woman who experienced her first clinical symptoms at age 55, including atypical alterations such as bradykinesia and mild action tremor (Clarimon et al., 2008; Guerreiro et al., 2010). Her father and grandmother were diagnosed with late-onset dementia.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Neuropathological data are unavailable.

Biological Effect

Experimental assays to assess how this variant affects APP processing have yielded mixed results, but most suggest a damaging effect. A study that examined a range of Aβ peptides generated by this variant in human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2, revealed decreased Aβ37/Aβ42, an indicator of reduced Aβ trimming activity which outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples (Liu et al., 2022; Apr 2022 news). It had little or no effect on the Aβ42/Aβ40 ratio and reduced production of all Aβ peptides measured—Aβ37, Aβ38, Aβ39, Aβ40, and Aβ42—except for Aβ43 which remained in the wild-type range. An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate also found decreased production of both the Aβ40 and Aβ42 peptides, but revealed an approximately two- to three-fold elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Moreover, structural modeling suggested the H214N substitution eliminates a hydrophobic interaction with PSEN1 W215, altering the stability and position of PSEN1’s transmembrane helix 4 in the plasma membrane (Bagyinszky et al., 2024).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). The mutation alters a residue conserved between PSEN1 and PSEN2 and was classified as possibly pathogenic (Guerreiro et al., 2010).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant 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. H214D: Experimental assays yielded mixed results, but most suggest a damaging effect.

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. H214D: Variant located at edge of mutational hot spot; cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 06 Mar 2024

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References

News Citations

Paper Citations

Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, Boada M, Bullido MJ, Ferrer I, Martínez-Lage P, Masdeu J, Molina L, Molinuevo JL, Pastor P, Pérez-Tur J, Rey MJ, Sánchez-Valle R, Tàrraga L, Valdivieso F, Singleton A, Hardy J. Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
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.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Bagyinszky E, Kim M, Park YH, An SS, Kim S. PSEN1 His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine-Tryptophan Interactions in TM-4 Stability. Int J Mol Sci. 2023 Dec 21;25(1) 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 H214D

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