Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Ataxia
Position: (GRCh38/hg38):Chr14:73173666 A>C
Position: (GRCh37/hg19):Chr14:73640374 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was detected in an Italian individual with early onset cognitive impairment associated with prominent cerebellar ataxia. The patient was 32 years old when she began to experience mild forgetfulness and compulsive behavior. Within months, significant motor problems developed involving both fine motor skills and gait. She developed myoclonic jerks and fell frequently. As cognitive impairment progressed, speech became progressively slower and slurred. By age 37 she was bedridden due to orthostatic hypotension. She developed generalized tonic-clonic seizures and bulbar symptoms. She died at age 40.

The patient did not have a family history of dementia or ataxia. Segregation of the T147P mutation with disease could not be assessed, but it was shown to be absent in 600 unrelated controls. Other genes known to cause cognitive impairment and/or ataxia were screened—APP, PSEN2, MAPT, PGRN, C9ORF72, PRNP, FRDA, SCA1, SCA2, SCA3, SCA17—no additional mutations were found (Testi et al., 2014).

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

Neuropathology

Although neuropathology data are unavailable, neuroimaging showed widespread cortical atrophy, as well as atrophy in the medial temporal lobes, with less severe cerebellar atrophy (Testi et al., 2014).

Biological Effect

In conditioned media of human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant, the Aβ42/Aβ40 was similar to that measured in the media of control cells, but the Aβ37/Aβ42 ratio was decreased, suggesting a damaging effect (Liu et al., 2022, Apr 2022 news). Of note, the Aβ37/Aβ42 ratio outperformed Aβ42/Aβ40 at distinguishing control versus AD samples.

Moreover, T147 closely contacts APP as revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment (Zhou et al., 2019; Jan 2019 news). Interestingly, the residue contributes to APP but not Notch binding (Yang et al., 2019).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Testi et al., 2014, Xiao et al., 2021).

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. T147P: In cells, decreased Aβ37/Aβ42 ratio, although Aβ42/Aβ40 was similar to controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. T147P: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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: 05 Jun 2022

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References

News Citations

Paper Citations

Testi S, Peluso S, Fabrizi GM, Antenora A, Russo CV, Pappatà S, Padovani A, Ferrarini M, Filla A. A novel PSEN1 mutation in a patient with sporadic early-onset Alzheimer's disease and prominent cerebellar ataxia. J Alzheimers Dis. 2014;41(3):709-14. PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Mutations

PSEN1 T147P

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