Overview

Pathogenicity: Amyotrophic Lateral Sclerosis : Not Classified, Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Amyotrophic Lateral Sclerosis
Reference Assembly: GRCh37/hg19
Position: Chr14:73659548 A>C
dbSNP ID: rs1363575880
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to CTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was found in a targeted sequencing screen of 169 genes in 242 patients with amyotrophic lateral sclerosis (ALS) from the Coriell collection of North American Caucasian DNA samples (Couthouis et al., 2014). The carrier was a man diagnosed with ALS (upper-limb onset), and no known family history of the disease. He was 63 years old at the time of sample collection. The mutation was absent from the ESP6500, 1000genomes, and dbSNPv137 databases.

The variant was also reported in a Chinese pedigree with familial early onset AD (Shen et al., 2019, Jia et al., 2020). The proband was a woman who presented with progressive memory loss at age 54. She later developed disorientation, personality changes, apathy, social withdrawal, and obsessive behaviors. She was homozygous for the APO E3 allele. Her mother was similarly affected by memory loss at age 54, followed by apathy and, in the later stages of disease, visual and auditory hallucinations. Cosegregation of the variant with disease was not established.

A single allele of this variant, found in a non-Finnish European individual, is reported in the gnomAD variant database resulting in a global frequency of 0.000003977 (gnomAd v2.1.1, July 2021). The variant was absent from the non-neuro gnomAD dataset which excludes data from neurological studies.

Neuropathology
Although neuropathological data are unavailable, brain MRI of the Chinese woman revealed hippocampal and cortical atrophy.

Biological Effect

Neuroblastoma cells expressing this mutation produced more Aβ42 and had an elevated Aβ42/Aβ40 ratio compared with cells expressing wildtype PSEN1 (Shen et al., 2019). The mutation did not affect PSEN1 endoproteolysis, nor Aβ43 production.

According to the PhyloP algorithm, the codon is evolutionarily conserved (Couthouis et al., 2014). However, some in silico predictions of the functional consequences of the mutation yielded mixed results (Couthouis et al., 2014, Jia et al., 2020, Xiao et al., 2021). Whereas SIFT predicted it to be tolerated, for example, PolyPhen2 classified it as possibly damaging, and Mutation Taster labeled it as disease causing (Couthouis et al., 2014). The PHRED-CADD score was 23.9 (Jia et al., 2020).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because only one carrier with AD has been reported—cosegregation data are lacking—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-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.

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

Couthouis J, Raphael AR, Daneshjou R, Gitler AD. Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet. 2014 Oct;10(10):e1004704. Epub 2014 Oct 9 PubMed.
Shen L, Qin W, Wu L, Zhou A, Tang Y, Wang Q, Jia L, Jia J. Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization. Biochem Biophys Res Commun. 2019 Aug 13;516(1):264-269. Epub 2019 Jun 21 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 I249L

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