Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3
Position: (GRCh38/hg38):Chr1:226890097 A>G
Position: (GRCh37/hg19):Chr1:227077798 A>G
dbSNP ID: rs1208742830
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGA to GGA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 9

Findings

This variant was originally identified in a screen of patients with early onset Alzheimer's disease from 28 French hospitals (Lanoiselée et al., 2017). Families were included when at least two first-degree relatives, spanning two generations, suffered from early onset AD with an age of onset of 65 years or younger. The proband's age at onset was 57 years, and disease duration was six years. 

It was also reported in an individual with early onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry (Hsu et al., 2018). The individual had an age at onset of 58 years. One of their parents and a sibling of their parents was also affected by AD.

The variant was absent from the EVS and ExAC variant databases.

Neuropathology
Unknown.

Biological Effect
Mouse neuroblastoma cells expressing APP695 (N2A695) and the PSEN2 R284G variant produced more Aβ42 and had a higher Aβ42/Aβ40 ratio than N2A695 cells expressing wild-type PSEN2. In silico algorithms predicted R284G to be probably damaging (PolyPhen) and damaging (SIFT), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). In addition, R284 is conserved between PSEN2 and PSEN1. Based on their pathogenicity classification scheme, Hsu and colleagues described it as probably pathogenic (Hsu et al., 2018; Hsu et al., 2020).

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.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
2. 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.
3. 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