Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637725 T>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to GGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This mutation was found in a screen of APP, PSEN1, and PSEN2 genes of 148 Chinese patients with familial AD who had at least two first-degree relatives with dementia (Gao et al., 2019).  The carrier of this mutation was a man who developed AD symptoms at age 42, and by age 44 was experiencing memory loss, executive dysfunction, disorientation, and dyscalculia. He was homozygous for APOE3. The mutation was absent from the gnomAD variant database.


Biological Effect
The biological effect of this mutation is unknown. Analysis of a high-resolution cryo-EM structure of the human γ-secretase revealed this substitution likely decreases interaction with other hydrophobic residues (Gao et al., 2019Bai et al., 2015). Also, orthologous sequence alignments revealed V103 is an evolutionarily conserved residue. Moreover, Gao and colleagues reported predictions of probably damaging (PolyPhen), affecting protein function (SIFT), and disease-causing (MutationTaster), with a CADD score of 28.2, although Xiao and colleagues reported conflicting results using SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database (Xiao et al., 2021). Gao and co-workers classified the mutation as “probably pathogenic,” following the algorithm by Guerreiro et al., 2010.

Last Updated: 09 Sep 2021


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Paper Citations

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
  2. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  3. . 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.
  4. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.

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