Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP2, PP3, BS1, BS2, BS3, BS4
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr14:73673178 A>G
dbSNP ID: rs17125721
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9
This variant was initially found in people with early onset AD (e.g., Taddei et al., 2002; Albani et al., 2007); however, it did not segregate with disease. It was also identified in individuals with late-onset AD and in healthy controls (e.g., Mattila et al., 1998; Dermaut et al., 1999; Aldudo et al., 1998; Zekanowski et al., 2004; Helisalmi et al., 2000; Perrone et al., 2020; Mathioudakis et al., 2022). It is present in the gnomAD variant database at a frequency of 0.015 with an allele count of 4,197 (gnomAD v2.1.1, August 2021). Moreover, in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, the frequency was 0.022 (HEX, August 2020). Also, two of the larger published studies failed to reveal a link between the variant and AD risk (Hippen et al., 2016, Perrone et al., 2020).
In a study of individuals of Spanish descent, this variant was detected in two of 176 individuals with AD and three of 139 controls (Jin et al., 2012). The cases with AD were described as having sporadic early onset AD, with onset at 56.5 and 65.5 years of age. Further clinical details were not reported. The presence of this variant in controls led the authors to classify the variant as not pathogenic.
The E318G variant was later found in about 5 percent of families affected by familial late onset AD (30 out of 565 families). The variant was more frequently found in cases of familial late-onset AD (LOAD) than in cases of "sporadic" LOAD (Benitez et al., 2013). This mutation also turned up in a study that sequenced AD-associated genes in people with extreme biomarker levels of in their cerebrospinal fluid (Benitez et al., 2013; Sep 2013 news). Specifically, the E318G variant was associated with high levels of total tau and phospho-tau. In carriers of the LOAD risk allele APOE4, it was also associated with Aβ deposition and faster cognitive decline. Furthermore, at least two studies reported that APOE4 carriers who also carried the E318G variant were at greater risk of developing late-onset AD, than APOE4 carriers without the variant (Benitez et al., 2013; Nho et al., 2016). In addition, in a study of 72 AD cases and 58 controls, the E318G variant was detected in one individual with AD and in one control, the latter lacking significant AD neuropathology postmortem. Additional information regarding these two mutation carriers, including their ages, was not reported (Frigerio et al., 2015).
Subsequently, a study of two Brazilian cohorts, including 53 individuals with a familial history of AD and 120 with sporadic AD, concluded that the E318G variant increases AD risk (Abdala et al., 2017). In familial AD cases, the odds ratio was 6.0 (IC95%=1.06-33.79; p=0.042). Also, a study of Caribbean Hispanics, including three families carrying the E381G variant, reported an association with AD risk and an elevated hazard ratio with a wide confidence interval (Lee et al., 2014). However, a study of 3420 American individuals, including 478 diagnosed with AD, found no significant association (Hippen et al., 2016). In this study, a Fisher's exact test suggested APOE4 carriers with an E318G allele had a slightly higher risk of AD than those without the allele, but the effect did not reach statistical significance. Likewise, a logistic regression model found a positive, but non-significant E318G effect. Neither the Brazilian nor the American studies found an interaction between E318G and APOE4. Similarly, a study of Belgian individuals identified the variant in 45 of 1,431 AD patients and in 24 of 809 controls. An association with AD was not detected, regardless of APOE genotype (Perrone et al., 2020).
One study identified this variant as being associated with an AD age at onset that was earlier than expected based on carriers’ parental age at onset, although inter-individual variability was high (z-score of residual SD = -1.04, range= -2.13-0.64; Day et al., 2019).
The E318G variant has also been implicated in increasing the risk of dementia with Lewy bodies. In a cohort of 111 pathologically confirmed cases of this disease, 10 individuals carried the mutation, a frequency much higher than seen in controls (Geiger et al., 2016).
E318G has also been identified in individuals carrying other variants in PSEN1 or in other genes implicated in AD or other neurodegenerative disorders, where it has been hypothesized to exert a modifying effect (Coppola et al., 2020; Eryilmaz et al., 2021; Bisceglia et al., 2022; Yang et al., 2023).
Although some carriers have AD neuropathology, at least one carrier was reported to lack it (Frigerio et al., 2015). Moreover, studies of the biomarker profiles of E318G carriers have yielded mixed results. Although one study reported increased tau and phospho-tau levels in CSF from carriers (Benitez et al., 2013), no changes in these CSF biomarkers, nor in Aβ42, were found in asymptomatic members of a large Italian family, although plasma Aβ40 levels were increased (Artuso et al., 2019). A more recent study of 20 Belgian carriers found a reduction in both Aβ42 and Aβ43 CSF levels, with a decrease in the Aβ43/Aβ42, Aβ43/Aβ40, and Aβ42/Aβ40 ratios (Perrone et al., 2020). Interestingly, in this study, the CSF profiles of E318G carriers shared similarities with those of known pathogenic mutation carriers, as well as with those of controls. In particular, carriers of known pathogenic mutations or E318G could be distinguished from controls based on their CSF Aβ43 and Aβ42 levels, which positively correlated with each other. However, Aβ43 and Aβ42 levels correlated with Aβ40 in both E318G carriers and controls, but not in carriers of known pathogenic mutations. Also, CSF sAPPα and sAPPβ levels were reduced in E318G carriers, as were Aβ43/sAPPα and Aβ43/sAPPβ ratios. Although similar alterations were observed in pathogenic mutation carriers, they failed to reach statistical significance. The biological meaning of these reductions remains unclear given that sAPPα and sAPPβ are generated by α- and β-secretase, rather than γ-secretase.
The most recent, in-depth studies of Aβ peptide generation indicate this variant has no deleterious effect. In cells transfected with E318G, two peptide ratios that outperformed the Aβ42/Aβ40 ratio as indicators of AD pathogenicity—Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42—were similar to those of cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Indeed, one of these studies used the E318G variant as a nonpathogenic control (Petit et al., 2022). These findings are consistent with a report focusing only on Aβ40 and Aβ42 which showed that, in mouse neuroblastoma cells expressing E318G, neither Aβ42 levels nor the Aβ42/Aβ40 ratio were elevated compared with wildtype PSEN1 (Hsu et al., 2020).
Earlier studies, however, reported mixed effects. In HEK293 cells transfected with PSEN1 E318G, secretion of both Aβ40 and Aβ42 peptides was reported as robustly increased compared to controls (Bialopiotrowicz et al., 2012). Moreover, in experiments using isolated proteins, Aβ40 and Aβ42 production was reduced to undetectable levels (Sun et al., 2017).
Structural modeling predicted this substitution, in an evolutionarily non-conserved residue, is unlikely to result in substantial structural alterations, although it might alter the flexibility of a potental loop formed with N318 (Yang et al., 2023). Several in silico algorithms (LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, REVEL, and Reve in the VarCards database) yielded conflicting predictions regarding the effects of this variant (Xiao et al., 2021), but the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).
Using their pathogencity guidelines, Hsu and colleagues classified E318G as "not pathogenic" (Hsu et al., 2020).
Alzheimer's Disease : Benign*
*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
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.
Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. E318G: Although early studies yielded mixed results, most evidence indicates this variant does not significantly affect A peptide production.
Lack of segregation in affected members of a family.
|Pathogenic (PS, PM, PP)||Benign (BA, BS, BP)|
|Criteria Weighting||Strong (-S)||Moderate (-M)||Supporting (-P)||Supporting (-P)||Strong (-S)||Strongest (BA)|
Last Updated: 01 Nov 2023
- Going to Biomarker Extremes to Find Rare Alzheimer’s Variants
- Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
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