Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227083176 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to TCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13

Findings

This variant was found in a whole-exome sequencing screen for rare variants in genes associated with Alzheimer's disease (AD), frontotemporal dementia, and prion disease in a Dutch cohort of 68 patients with early onset AD (Wong et al., 2020).

The proband was a woman who initially presented with memory loss and a spastic gait at age 59. She later developed difficulties with verbal expression, hallucinations, and myoclonus. At 65, she became mute and wheelchair-bound. Her grandmother, aunt, and uncle also had dementia, but their disease onset occurred later, when they were over 65 years old.

This variant was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology
Neuropathological data are unavailable, but an MRI brain scan of the proband showed global cerebral and cerebellar atrophy (Wong et al., 2020). Moreover, levels of Aβ, phospho-tau, and tau levels, were consistent with AD.

Biological Effect
The biological effect of this variant is unknown, but it is conserved in PSEN1, corresponding to A431, the location of well-characterized pathogenic variant A431E. Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (Wong et al., 2020). Wong and colleagues classified the variant as probably pathogenic using the Guerreiro et al., 2010 guidelines.

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.

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.

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

Mutations Citations

Paper Citations

Wong TH, Seelaar H, Melhem S, Rozemuller AJ, van Swieten JC. Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations. Neurobiol Aging. 2020 Feb;86:201.e9-201.e14. Epub 2019 Jan 29 PubMed.
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.

Mutations

PSEN2 A415S

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