Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP2, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192754 G>A
Position: (GRCh37/hg19):Chr14:73659462 G>A
dbSNP ID: rs763831389
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGA to CAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

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 global frequency of 0.0000074, including 12 heterozygotes (gnomAD v.4.0.0, Jan 2024). Although most of these carriers (7) were of non-Finnish European ancestry, the variant's frequency was higher in other groups, with 2 carriers of African ancestry yielding an allele frequency of 0.000027 in that population.

Neuropathology
Neuropathological data are unavailable.

Biological Effect
The biological effect of this variant is unknown, however, in silico algorithms predicted it is damaging (PHRED-scaled CADD score = 22.9; 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 fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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. R220Q: Most carriers were of European ancestry, but frequency was higher in individuals of African 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: 26 Jan 2024

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References

Paper Citations

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.

Mutations

PSEN1 R220Q

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