Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73171032 G>A
Position: (GRCh37/hg19):Chr14:73637740 G>A
dbSNP ID: rs200646139
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

The R108Q variant was reported in a Serbian individual with a family history of early onset Alzheimer’s disease (Dobricic et al., 2012). The proband experienced symptom onset at age 45, including progressive cognitive deterioration and myoclonic jerks. His mother had died at age 60 with a diagnosis of probable AD. Segregation with disease could not be determined due to lack of DNA from family members. Notably, this proband also carried a known pathogenic APP mutation, L723P, which may account for his disease.

The variant was described as most likely having reduced penetrance, with an allele count of two, and a frequency of 0.0008 percent in the gnomAD variant database (Koriath et al., 2018). It was absent from the ExAC and EVS variant databases, however, which, unlike gnomAD, do not include sequencing data from the Alzheimer's Disease Sequencing Project (Hsu et al., 2020).

Neuropathology

Unknown.

Biological Effect

Mouse neuroblastoma cells expressing APP695 (N2A695) and the PSEN1 R108Q variant, but lacking PSEN1 and PSEN2 endogenous expression, produced more Aβ42 and Aβ40 than N2A695 cells expressing wild-type PSEN1 (Hsu et al., 2020). The Aβ42/Aβ40 ratio was modestly increased but not significantly different from wild-type. In contrast, production of Aβ40 was reported as undetectable and that of Aβ42 as reduced in an in vitro assay using purified proteins to test the ability of the variant to cleave the APP-C99 substrate (Sun et al. 2017).

Although the residue is not conserved between PSEN1 and PSEN2 and a study using multiple in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) reported conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score, above 20 (CADD v.1.6, Sep 2021). Based on their guidelines, Hsu and colleagues classified this variant as probably pathogenic (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. R108Q: Functional observations are mixed, but overall they suggest damaging effects.

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: 22 Feb 2022

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References

Paper Citations

Dobricic V, Stefanova E, Jankovic M, Gurunlian N, Novakovic I, Hardy J, Kostic V, Guerreiro R. Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort. Neurobiol Aging. 2012 Jul;33(7):1481.e7-12. Epub 2012 Jan 4 PubMed.
Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
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.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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 R108Q

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