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):Chr14:73171047 T>A
Position: (GRCh37/hg19):Chr14:73637755 T>A
dbSNP ID: rs63751399
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTA to CAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation, located in the first hydrophilic loop of the presenilin-1 protein, was detected in a Greek patient identified as p.62. She experienced symptom onset at age 33 and died three years later. Prominent symptoms included rapidly progressing dementia, drop attacks, myoclonic seizures, and bilateral spasticity. The patient had a family history of very early onset dementia. The patient’s brother and mother died at ages 35 and 36, respectively, and the family indicated that her maternal grandfather and uncle had had similar disease courses (Finckh et al., 2005).

The variant was absent from the gnomAD variant database (May 2021).

Neuropathology

Autopsy confirmed the diagnosis of Alzheimer’s disease, reporting neuritic plaques (Braak stage C), neurofibrillary tangles (stage VI), and severe amyloid angiopathy (Finckh et al., 2005).

Biological Effect

L113 has been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species (Liu et al., 2021). Consistently, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 production resulting in an approximately 5-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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 (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-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L113Q: Variant located at edge of mutational hot spot.

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: 22 Feb 2022

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References

Paper Citations

Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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 L113Q

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