Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226888974 C>T
Position: (GRCh37/hg19):Chr1:227076675 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to TTC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant was first detected in an individual with apparently sporadic AD (Frigerio et al., 2015). There was no family history of dementia. Other than the diagnosis, clinical details related to this individual were not reported. 

The variant was also found in a patient with early onset AD whose symptoms emerged in their 50s (Wright et al., 2023), as well as in a case of late-onset AD (Wang et al., 2023, suppl table e-5). The latter case was reported in a preprint that analyzed data from the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 13,825 late-onset AD cases and 14,715 controls. The variant was absent from controls.

L238F has also been reported in a study of six pedigrees with early onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry (Hsu et al., 2018). The proband’s age at onset was 49, while that of one of the parents was 57. The family included affected individuals spanning three generations.

Two L238F alleles were reported in the EVS and ExAC variant databases (Hsu et al., 2018). More recently, in the gnomAD database, the variant was reported at a frequency of 0.000042, including 68 heterozygote carriers, all except one of European (non-Finnish) ancestry (v4.0.0, Jan 2024).

Neuropathology

Neuropathological data are unavailable. One healthy carrier, 17 years younger than the parental age at onset, had cerebrospinal fluid levels of Aβ, total tau, and phosphorylated tau that were comparable to those of controls (Hsu et al., 2018).

Biological Effect

Although one study reported that mouse neuroblastoma cells expressing this variant produced Aβ42 and Aβ40 at levels similar to cells expressing wild-type PSEN2 (Hsu et al., 2018), a subsequent study from the same group reported a nearly 2-fold increase in the Aβ42/Aβ40 ratio compared with cells transfected with wildtype PSEN2 (Hsu et al., 2020). Of note, the neuroblastoma cells used in the 2020 study lacked endogenous PSEN1 and PSEN2.

Although in silico algorithms yielded mixed results, with one predicting the mutation is probably damaging (PolyPhen) and another predicting it is tolerated (SIFT), the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). Its metaSVM score (dbNFSP v. 4.3a) also predicted a damaging effect (Wang et al., 2023). Moreover, residue L238 is conserved between PSEN1 and PSEN2.

Hsu and colleagues had originally classified L238F as an AD risk factor or a benign polymorphism (Hsu et al., 2018), but updated their classification to probably pathogenic based on their new findings (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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

Paper Citations

1. Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.
2. Wright CA, Taylor JW, Cochran M, Lawlor JM, Moyers BA, Amaral MD, Bonnstetter ZT, Carter P, Solomon V, Myers RM, Love MN, Geldmacher DS, Cooper SJ, Roberson ED, Cochran JN. Contributions of rare and common variation to early-onset and atypical dementia risk. Cold Spring Harb Mol Case Stud. 2023 Jun;9(3) Print 2023 Jun PubMed.
3. 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.
4. Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.
5. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading