Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659517 C>G
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to ATG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This variant was found in a 60-year-old man with a family history of dementia, including four affected members (Wojtas et al., 2012). He was part of a cohort with onset of clinical probable Alzheimer’s disease (AD) before age 70 at the Mayo Clinic in Jacksonville, Florida. Members of the cohort were screened for mutations in genes associated with AD and frontotemporal dementia (exon 16 and 17 of APP, exons 3-12 of PSEN1, and exons 3-12 of PSEN2). His first symptoms were memory and vision loss and his APOE genotype was E3/E4.

The variant was also identified in an African-American woman diagnosed with probable AD who had a family history of AD/dementia (Ting et al., 2014). Her presentation was fairly typical of AD, starting with short-term memory loss, poor concentration, an inability to multitask, and increased anxiety. These symptoms began at age 50 and gradually progressed to multiple cognitive domains and impairment of activities of daily living. This patient was enrolled in the longitudinal study, the Dominantly Inherited Alzheimer Network (DIAN).

The patient's father was diagnosed with AD in his late 50s and died at the age of 65. Her paternal aunt and grandmother also died with dementia, but age of onset and age at death were not known. It was not possible to confirm disease segregation in this family, as DNA was not available from other affected members (who were all deceased) or unaffected members of the family.

This variant was absent from more than 2,000 African-Americans screened in the NHLBI GO sequencing project and from the gnomAD variant database (gnomAD v2.1.1, July 2021).


Unknown; MRI showed progressive cerebral atrophy. PET showed hypometabolism in the frontal and temporal lobes.

Biological Effect

When expressed in HEK293 cells expressing APP with the Swedish mutation, the mutant PSEN1 increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1 (Ting et al., 2014; see also Ringman et al., 2011). Consistent with these findings, a subsequent study in HEK cells expressing only the PSEN1 I238M mutation, also revealed an increased Aβ42/Aβ40 ratio, while the ratio of short to long Aβ species was decreased (Schultz et al., 2023). In this study, an indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 48.76 for I238M, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

Although in an in vitro assay using purified proteins to test the mutant's ability to cleave APP-C99, I238M appeared to abrogate production of both Aβ40 and Aβ42 (Sun et al., 2017), this assay's ability to recapitulate physiological cleavage efficiency appears to be limited (Liu et al., 2021).

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).

Probable pathogenicity was suspected based on the early onset of symptoms, the family history of dementia, the absence of the mutation in variant databases, and the effects on Aβ levels in cultured cells (Ting et al., 2014).


Alzheimer's Disease : Likely 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. I238M: Functional observations are mixed, but most data indicate a damaging effect.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. I238M: Variant located at edge of mutational hot spot.


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.


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: 17 Oct 2023


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Mutations Citations

  1. APP K670_M671delinsNL (Swedish)

Paper Citations

  1. . C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16 PubMed.
  2. . A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer's disease in an African-American woman. J Alzheimers Dis. 2014;40(2):271-5. PubMed.
  3. . Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation. Neurosci Lett. 2011 Jan 10;487(3):287-92. Epub 2010 Nov 19 PubMed.
  4. . Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
  5. . 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.
  6. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  7. . 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. the Dominantly Inherited Alzheimer Network (DIAN)
  2. NHLBI GO sequencing project
  3. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer's disease in an African-American woman. J Alzheimers Dis. 2014;40(2):271-5. PubMed.


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