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., 2023). While the Aβ42/Aβ40 ratio was increased, the ratio of short to long Aβ species was decreased, indicating a damaging effect. An indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 38.92 for L291P, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

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.

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References

Mutations Citations

1. PSEN1 E318G

Paper Citations

1. 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.
2. 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.
3. Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
4. 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading