Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Spastic Paraparesis : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198094 G>A
Position: (GRCh37/hg19):Chr14:73664802 G>A
dbSNP ID: rs63749891
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGA to AAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in three individuals in the same family who developed a diverse set of symptoms in their 40s (Assini et al., 2003). One woman initially presented with progressive paraperesis, developing dementia five years later. Her daughter, on the other hand, suffered from delusional thinking followed by progressive cognitive decline, without apparent motor symptoms. Moreover, her brother was first diagnosed with spastic paraperesis and 12 years later developed difficulty recalling words, with no other apparent cognitive impairment. The mutation was absent from 150 healthy controls and from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Although neuropathology data are unavailable, the brother was reported as having normal MRI and CT scans.

Biological Effect

Increased Aβ42 was detected in the conditioned medium of fibroblasts from the two siblings, while Aβ40 levels were similar to controls (Assini et al., 2003). However, another study reported reduced Aβ42 and Aβ40 production using purified proteins to test the ability of the mutant to cleave the APP-C99 substrate in vitro (Sun et al., 2017). In both studies, the Aβ42/Aβ40 ratio was increased relative to controls.

As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, R278 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019 news). Moreover, 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). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because the reported carriers had heterogenous phenotypes and the variant's relationship to AD was unclear.

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. R278K: Aβ42/Aβ40 ratio increased in two assays, but observations on the production of both peptides were mixed.

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. R278K: 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.

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: 28 Feb 2022

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References

News Citations

Paper Citations

Assini A, Terreni L, Borghi R, Giliberto L, Piccini A, Loqui D, Fogliarino S, Forloni G, Tabaton M. Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology. 2003 Jan 14;60(1):150. 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.
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.
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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 R278K

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