Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226881993 G>A
Position: (GRCh37/hg19):Chr1:227069694 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 4

Findings

This variant was originally identified in an African individual from the Mandenka population (Guerreiro et al., 2010), and subsequently found in three of 95 patients with Alzheimer's disease (AD) from the Cretan Aging Cohort (Mathioudakis et al., 2022). All three of the Cretan patients had late ages of disease onset: 76, 78, and 104 years. The variant was absent from 81 Cretan controls and 20 Cretan patients with mild cognitive impairment. Three heterozygotes, all of African ancestry, were reported in the gnomAD variant database (v2.1.1, Oct 2021). The variant's global frequency was 0.000012. 

Neuropathology

Neuropathological data are unavailable.

Biological Effect

The biological effects of this variant are unknown, but R29 is evolutionarily conserved and R29H's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (21.6), suggesting a deleterious effect (Mathioudakis et al., 2022). The in silico algorithm Polyphen predicted it is probably damaging, but SIFT predicted it is tolerated (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. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
2. Mathioudakis L, Dimovasili C, Bourbouli M, Latsoudis H, Kokosali E, Gouna G, Vogiatzi E, Basta M, Kapetanaki S, Panagiotakis S, Kanterakis A, Boumpas D, Lionis C, Plaitakis A, Simos P, Vgontzas A, Kafetzopoulos D, Zaganas I. Study of Alzheimer's disease- and frontotemporal dementia-associated genes in the Cretan Aging Cohort. Neurobiol Aging. 2023 Mar;123:111-128. Epub 2022 Jul 11 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.

External Citations

1. Mathioudakis et al., 2022

Further Reading

No Available Further Reading