Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659443 C>T
dbSNP ID: rs63751003
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to TAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was originally detected in a French family (Alz 178) with at least five family members affected by early onset Alzheimer’s disease. Onset in this family occurred at 37 to 45 years of age. Inheritance was reported as autosomal dominant, but details of the segregation with disease were not reported (Raux et al., 2005).

H214Y was also identified in an Iranian patient with a positive family history of dementia. The family, known as DEM12, had at least seven members affected by dementia, with a notably variable clinical phenotype. The proband developed symptom onset at the age of 51, starting with apathy and depression. Progressive memory impairment followed, along with disorientation to time and space, non-fluent aphasia, and myoclonic jerks. Five years after onset he was severely demented with visual hallucinations and stereotypic behavior. The clinical phenotype in this family was variable. The proband's mother was alive at the time of the report, living with frontotemporal dementia at the age of 81. The proband's aunt and two cousins were affected by Parkinson's disease with dementia, an uncle had dementia, and a grandfather had AD. Segregation of H214Y with disease could not be determined due to lack of DNA from family members (Lohmann et al., 2012).

More recently, this variant was reported in a large prospective study of French patients with AD (Nicolas et al., 2024). The proband was a woman with symptoms emerging at age 50 and with disease duration of nine years. She was homozygous for APOE3. Her brother was also a carrier with symptoms arising at age 54. Although not genotyped, their paternal grandmother was affected with symptoms emerging before age 65. The father was unaffected but he died at age 46, before the average age at onset.

Of note, an individual diagnosed with sporadic late-onset AD was also found to carry this variant. The patient was a member of a case-control cohort of the AD Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 5,844 cases and 4,767 controls, most of European-American ancestry (Fernández et al., 2017; see also Wang et al., 2023).

This variant is found at a frequency of 0.000004, with an allele count of only 1, in the gnomAD variant database (gnomAD v2.1.1, Sep 2021).

Neuropathology

Neuropathological data are unavailable. Imaging of the Iranian proband one year after symptom onset, at age 52, showed global cortical atrophy with marked frontotemporal atrophy and white-matter lesions (Lohmann et al., 2012). Moreover, four years after symptom onset, at age 54, one of the French carriers had diffuse cortical atrophy predominantly in the left hemisphere (Nicolas et al., 2024).

Biological Effect

A study that examined a range of Aβ peptides generated by this variant in human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this mutant revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.

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). The change in aromatic side chains resulting from the H214Y substitution, from positively charged to uncharged, was predicted to be disruptive (Bagyinszky et al., 2024).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021, Lohmann et al., 2012). It was classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012).

Pathogenicity

Alzheimer's Disease : Pathogenic

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

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. H214Y: Variant is at edge of a 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: 12 Mar 2024

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References

News Citations

Paper Citations

Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
Lohmann E, Guerreiro RJ, Erginel-Unaltuna N, Gurunlian N, Bilgic B, Gurvit H, Hanagasi HA, Luu N, Emre M, Singleton A. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
Nicolas G, Zaréa A, Lacour M, Quenez O, Rousseau S, Richard AC, Bonnevalle A, Schramm C, Olaso R, Sandron F, Boland A, Deleuze JF, Andriuta D, Anthony P, Auriacombe S, Balageas AC, Ballan G, Barbay M, Béjot Y, Belliard S, Benaiteau M, Bennys K, Bombois S, Boutoleau-Bretonnière C, Branger P, Carlier J, Cartz-Piver L, Cassagnaud P, Ceccaldi MP, Chauviré V, Chen Y, Cogez J, Cognat E, Contegal-Callier F, Corneille L, Couratier P, Cretin B, Crinquette C, Dauriat B, Dautricourt S, de la Sayette V, de Liège A, Deffond D, Demurger F, Deramecourt V, Derollez C, Dionet E, Doco Fenzy M, Dumurgier J, Dutray A, Etcharry-Bouyx F, Formaglio M, Gabelle A, Gainche-Salmon A, Godefroy O, Graber M, Gregoire C, Grimaldi S, Gueniat J, Gueriot C, Guillet-Pichon V, Haffen S, Hanta CR, Hardy C, Hautecloque G, Heitz C, Hourregue C, Jonveaux T, Jurici S, Koric L, Krolak-Salmon P, Lagarde J, Lanoiselée HM, Laurens B, Le Ber I, Le Guyader G, Leblanc A, Lebouvier T, Levy R, Lippi A, Mackowiak MA, Magnin E, Marelli C, Martinaud O, Maureille A, Migliaccio R, Milongo-Rigal E, Mohr S, Mollion H, Morin A, Nivelle J, Noiray C, Olivieri P, Paquet C, Pariente J, Pasquier F, Perron A, Philippi N, Planche V, Pouclet-Courtemanche H, Rafiq M, Rollin-Sillaire A, Roué-Jagot C, Saracino D, Sarazin M, Sauvée M, Sellal F, Teichmann M, Thauvin C, Thomas Q, Tisserand C, Turpinat C, Van Damme L, Vercruysse O, Villain N, Wagemann N, Charbonnier C, Wallon D. Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening. Genet Med. 2024 May;26(5):101082. Epub 2024 Jan 24 PubMed.
Fernández MV, Kim JH, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A, NIA-LOAD family study group, NCRAD, Cruchaga C. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet. 2017 Nov;13(11):e1007045. PubMed.
Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
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.
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.
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.

Mutations

PSEN1 H214Y

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