Pathogenicity: Amyotrophic Lateral Sclerosis : Unclear Pathogenicity, Alzheimer's Disease : Pathogenic
Clinical Phenotype: Amyotrophic Lateral Sclerosis, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659548 A>C
dbSNP ID: rs1363575880
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATC to CTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7


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 mutation was also reported in a Chinese pedigree with familial early onset AD (Shen et al., 2019). 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. 

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). The site is flanked by amino acids for which several mutations have been reported.  However, in silico predictions of pathogenicity yielded mixed results. Whereas SIFT predicted it to be tolerated, PolyPhen2 classified it as possibly damaging, and Mutation Taster labeled it as disease causing.

Last Updated: 16 Aug 2019


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Paper Citations

  1. . Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet. 2014 Oct;10(10):e1004704. Epub 2014 Oct 9 PubMed.
  2. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet. 2014 Oct;10(10):e1004704. Epub 2014 Oct 9 PubMed.

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