Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226889035 C>T
Position: (GRCh37/hg19):Chr1:227076736 C>T
dbSNP ID: rs14443227784
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to GTC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant was found in a Japanese individual diagnosed with probable AD and a family history of dementia (Yagi et al., 2014). The mutation was absent from 112 Japanese controls and from 147 patients with diseases other than AD. It was also absent from the variant databases gnomAD, dbSNP137, and 1000 genomes.

Neuropathology
Unknown.

Biological Effect
In mouse neuroblastoma cells expressing this variant on a PSEN1/PSEN2 null background, Aβ40 and Aβ42 secretion were reduced, and the Aβ42/Aβ40 ratio was unchanged compared with cells expressing wildtype PSEN2 (Hsu et al., 2020).

Moreover, A258 is not conserved between PSEN2 and PSEN1, and the variant was not predicted to be pathogenic by either SIFT, PolyPhen2, or Pmut (Yagi et al., 2014, Hsu et al., 2020). However, the CADD tool, which integrates diverse information in silico, predicted a damaging effect, with a PHRED-scaled CADD score of 21.2, slightly above 20, a commonly used threshold for assessing deleteriousness(CADD v.1.6, Nov 2021). Hsu and colleagues classified this variant as "not 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.

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.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

	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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

Yagi R, Miyamoto R, Morino H, Izumi Y, Kuramochi M, Kurashige T, Maruyama H, Mizuno N, Kurihara H, Kawakami H. Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 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.

Mutations

PSEN2 A258V

Quick Links