Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637706 G>T
dbSNP ID: rs63750852
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This rare missense mutation was identified in a Han Chinese family. The reported pedigree consisted of three affected individuals over four generations. The affected family members were diagnosed with probable Alzheimer's disease according to NINCDS-ADRDA criteria. The mean age of onset was 36.5 ± 15.9 years. The mutation was present in all three affected individuals and absent in five healthy family members and 50 healthy unrelated controls (Jia et al., 2005). In a subsequent study, the same research group reported a family from the Chinese Familial Alzheimer's Disease Network with five affected members spanning three generations with a mean age at onset of 51 years (Jia et al., 2020).

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


Postmortem analysis was unavailable, but MRI from two mutation carriers showed enlarged lateral ventricles and atrophy of the cerebral cortex, especially the temporal lobes (Jia et al., 2005).

Biological Effect

Human neuroblastoma cells (SH-SY5Y) transfected with V97L PSEN1 had elevated intracellular and extracellular Aβ42 compared to mock-transfected cells and those expressing wild-type PSEN1 (Fang et al., 2006). However, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed slight decreases in both Aβ40 and Aβ42 production, with a Aβ42/Aβ40 ratio similar to that of wildtype PSEN1 (Sun et al., 2017). Interestingly, a subsequent study using human embryonic kidney cells, also found the Aβ42/Aβ40 ratio to be similar to controls as well as levels of both peptides (Liu et al., 2022, Apr 2022 news). However, Aβ37 levels were decreased and the Aβ37/Aβ42 ratio, which outperformed Aβ42/Aβ40 in distinguishing control versus AD samples, was also decreased, suggesting a deleterious effect. 

Other effects reported for this mutation include decreased expression and activity of insulin-degrading enzyme in the cytosol and endoplasmic reticulum (Qin and Jia, 2008), enhanced sensitivity to trophic withdrawal (Fang and Jia, 2008), and disruption of intracellular calcium homeostasis (Wang et al., 2015; Tong et al., 2016Sep 2016 news).

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)


Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. V97L: MIxed experimental results, but a detailed analysis of Aβ peptide production in cells indicated a deleterious effect including a decreased Aβ37/Aβ42 ratio. Alterations of other cellular functions were also reported.


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


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.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. V97L: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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: 11 Apr 2022


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News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor

Paper Citations

  1. . One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer's disease. J Alzheimers Dis. 2005 Apr;7(2):119-24; discussion 173-80. PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . Chinese Presenilin-1 V97L mutation enhanced Abeta42 levels in SH-SY5Y neuroblastoma cells. Neurosci Lett. 2006 Oct 2;406(1-2):33-7. PubMed.
  4. . 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.
  5. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  6. . Down-regulation of insulin-degrading enzyme by presenilin 1 V97L mutant potentially underlies increased levels of amyloid beta 42. Eur J Neurosci. 2008 May;27(9):2425-32. PubMed.
  7. . Human neuroblastoma cells transfected with two Chinese presenilin 1 mutations are sensitized to trophic factor withdrawal and protected by insulin-like growth factor-1. Chin Med J (Engl). 2008 May 20;121(10):910-5. PubMed.
  8. . FAD-linked Presenilin-1 V97L mutation impede tranport regulation and intracellular Ca(2+) homeostasis under ER stress. Int J Clin Exp Med. 2015;8(11):20742-50. Epub 2015 Nov 15 PubMed.
  9. . Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal. 2016 Sep 6;9(444):ra89. PubMed.
  10. . 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.

External Citations

  1. gnomAD variant database

Further Reading

Protein Diagram

Primary Papers

  1. . One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer's disease. J Alzheimers Dis. 2005 Apr;7(2):119-24; discussion 173-80. PubMed.


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