Mutations

PSEN2 R435Q

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226895536 G>A
Position: (GRCh37/hg19):Chr1:227083237 G>A
dbSNP ID: rs201922151
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13

Findings

This variant was reported in a preprint that analyzed data from the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 13,825 late-onset AD cases and 14,715 controls. The variant was identified in three AD cases and was absent from controls (Wang et al., 2023, suppl table e-5).

In the gnomAD variant database, the variant was reported at a frequency of 0.000046, including 74 carriers, most of European (non-Finnish) ancestry (gnomAD v.4.0.0, Jan 2024).

Biological Effect
The biological effect of this variant is unknown, however, in silico algorithms predicted it is damaging (PHRED-scaled CADD score = 22.1; CADD v.1.6, Jan 2024; damaging metaSVM score from dbNFSP v. 4.3a, Wang et al., 2023).

Pathogenicity

Alzheimer's Disease : Uncertain Significance*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  R435Q: Most carriers were of European ancestry.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 16 Jan 2024

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References

Paper Citations

  1. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.

Further Reading

No Available Further Reading

Protein Diagram

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