Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192751 T>C
Position: (GRCh37/hg19):Chr14:73659459 T>C
dbSNP ID: rs63750761
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was initially found in an Australian woman of British ancestry with a family history of dementia, including nine affected relatives spanning five generations (Smith et al., 1999). At 47 years of age, the proband began experiencing memory loss and cognitive impairment, which progressed in a manner consistent with AD, with deficits in orientation, recall, and language. The mutation was also detected in an affected sister and an affected cousin of the proband, but not in 50 unrelated subjects.

A subsequent study reported this mutation in a Turkish woman with an AD age at onset of 52 years and a family history of the disease (Eryilmaz et al., 2021). Of note, this mutation carrier also had the PSEN1 E318G variant, which has been described as either benign or an AD risk modifier.

The L219P variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathological examination of the brain of the proband’s sister, who carried the mutation and died in a demented state at age 54, confirmed an AD diagnosis according to CERAD criteria. Amyloid plaques and neurofibrillary tangles were widespread, but most concentrated in the hippocampus where they were associated with moderate to severe neuronal loss. In addition, meningeal congophilic amyloid angiopathy was detected in the cortex and cerebellum, with moderate intracortical angiopathy. In the proband, PET and SPECT scans showed hypoperfusion and hypometabolism of the temporal lobes and the right parietal lobe.

Biological Effect

Amyloid β production was disrupted in HEK293 cells expressing this variant (Schultz et al., 2024; Aug 2024 conference news). While the Aβ42/Aβ40 ratio was increased, the ratio of short to long Aβ species was decreased, indicating a damaging effect. The Aβ (37 + 38 + 40) / (42 + 43) ratio was only 34.65 percent that of control cells expressing wildtype PSEN1. This ratio, originally proposed by Chávez-Gutiérrez and colleagues (Petit et al., 2022), was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Moreover, several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging, and 3D modeling predicted conformational changes (Eryilmaz et al., 2021, Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely 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.

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: 14 Sep 2024

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References

Mutations Citations

News Citations

Paper Citations

Smith MJ, Gardner RJ, Knight MA, Forrest SM, Beyreuther K, Storey E, McLean CA, Cotton RG, Cappal R, Masters CL. Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene. Neuroreport. 1999 Feb 25;10(3):503-7. PubMed.
Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.
Schultz SA, Liu L, Schultz AP, Fitzpatrick CD, Levin R, Bellier JP, Shirzadi Z, Joseph-Mathurin N, Chen CD, Benzinger TL, Day GS, Farlow MR, Gordon BA, Hassenstab JJ, Jack CR Jr, Jucker M, Karch CM, Lee JH, Levin J, Perrin RJ, Schofield PR, Xiong C, Johnson KA, McDade E, Bateman RJ, Sperling RA, Selkoe DJ, Chhatwal JP, Dominantly Inherited Alzheimer Network. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 2024 Sep;23(9):913-924. Epub 2024 Jul 26 PubMed.
Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 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 L219P

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