Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198084 G>A
Position: (GRCh37/hg19):Chr14:73664792 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant was found in a Brazilian individual with early onset Alzheimer’s disease (Takada et al., 2022). The carrier developed symptoms of depression and loss of episodic memory at age 45, followed by motor dysfunction, and obsessive-compulsive behaviors. At 47, they had language impairment, and at age 49, profound expressive aphasia. One of the proband’s parents, who died at 66, had AD with symptoms emerging at age 56.

The variant was absent from three large variant databases, gnomAD, ClinVar, and the exome variant server.

Neuropathology
Neuropathological data are unavailable, but a brain MRI of the proband showed atrophy of the hippocampi and temporoparietal cortex (Takada et al., 2022). Moreover, brain SPECT revealed hypoperfusion of the right posterior parietal cortex.

Biological Effect
An assay using neuroblastoma N2A cells lacking endogenous presenilin genes and expressing the A275T mutation revealed an increase in Aβ42 and Aβ40 levels without altering the Aβ42/Aβ40 ratio (Takada et al., 2022).

This residue is highly conserved between PSEN1 and PSEN2. Moreover, A275T’s PHRED-scaled CADD score (29.4), which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Dec 2022). The authors classified this variant as pathogenic based on the algorithm described by Hsu et al., 2018.

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.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. A275T: The Aβ42/Aβ40 ratio was unchanged, but production of both peptides increased.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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.

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

Last Updated: 17 Oct 2023

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References

Paper Citations

Takada LT, Aláez-Verson C, Burgute BD, Nitrini R, Sosa AL, Castilhos RM, Chaves MF, Longoria EM, Carrillo-Sánchez K, Brucki SM, Flores-Lagunes LL, Molina C, Olivares MJ, Ziegemeier E, Petranek J, Goate AM, Cruchaga C, Renton AE, Fernández MV, Day GS, McDade E, Bateman RJ, Karch CM, Llibre-Guerra JJ, Dominantly Inherited Alzheimer Network. Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America. Alzheimers Res Ther. 2022 Aug 5;14(1):108. PubMed.
Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

Mutations

PSEN1 A275T

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