Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73664775 G>A
dbSNP ID: rs63750900
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to CAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8


This mutation has been described in at least eight families worldwide. The age at onset has been described as particularly variable for carriers of this mutation, ranging from mid-40s to late 60s. The variant is present at a frequency of 0.000004 in the gnomAD variant database (Koriath et al., 2018), and only one allele is found in the ExAC database from an individual of African ancestry (ExAC v.10, Oct 2020).

This mutation was first described in a Caucasian American man who developed memory impairment at the age of 46. He died after a nine-year course of progressive dementia and met CERAD criteria for AD. His clinical phenotype included visual and auditory hallucinations and myoclonus He did not have seizures or extrapyramidal signs. His APOE genotype was ε4/ε4. The patient’s father died at the age of 61 after a five-year history of dementia. There was no further family history of dementia and segregation with disease could not be assessed (Gómez-Isla et al., 1997).

Two members of a Japanese family (Mat-1) were found to carry this mutation. They met NINCDS-ADRDA criteria for AD and had an average age at onset of 50 years. Further clinical details were not reported (Kamimura et al., 1998).

A U.K. family (Family 226) was identified with four affected individuals over three generations. The mean age of onset in this family was 53 years of age (range: 50 to 56). At least one member of this family had autopsy-confirmed AD (Janssen et al., 2003).

A second U.K. family has been reported with nine affected individuals over three generations in a pattern consistent with autosomal-dominant transmission. The proband presented with forgetfulness at the age of 66 and was diagnosed with probable AD. He later developed prominent visual agnosia. His mother had been diagnosed with AD at the age of 67 and died two years later. She was one of seven sisters, five of whom were reported to have had AD, as had the maternal grandfather. At the age of 69, the proband’s sister also developed memory impairment consistent with AD. The proband was determined to carry the R269H mutation, but segregation with disease could not be assessed due to lack of DNA from family members (Larner et al., 2007).

The mutation was also identified in four patients from three U.K. families in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London (Ryan et al., 2016). Age at onset ranged from 50 to 62. One of two patients examined had behavioral alterations, and one of two had myoclonus. A previous report from the same group described a 59-year-old man with cognitive decline starting at age 58 (Ryan et al., 2012). The man presented with a pronounced dysexecutive syndrome, mild episodic memory impairment, and relative preservation of parietal lobe function. Finger myoclonus was also reported. The family history of disease was unknown.

The mutation was also found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband presented with cognitive deficits typical of AD, without any atypical neurological features.

A French carrier with a family history of AD and onset at age 60 was also reported (Lanoiselée et al., 2017), as well as a Belgian carrier with AD onset before age 66 (Perrone et al., 2020).


Postmortem analysis in the first mutation carrier showed a high burden of Aβ and neurofibrillary tangles in cortical areas compared with other cases of similar age and APOE genotype (Gómez-Isla et al., 1997). In another case, MRI revealed prominent cerebellar, parieto-occipital and temporal lobar microbleeds sufficient to fulfill criteria for probable cerebral amyloid angiopathy (Ryan et al., 2012). The authors hypothesized that the patient’s atypical phenotype, with early dysexecutive syndrome, could be related to this pathology. In addition, mild generalized volume loss, without predominance of medial temporal lobe atrophy, and moderate white matter disease were observed. MRI in another patient showed global brain atrophy and white-matter changes thought to be associated with the patient’s visual agnosia (Larner et al., 2007).

In another carrier, Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ levels in cerebrospinal fluid (CSF) were found to be reduced, as was the Aβ42/Aβ40 ratio, while tau and phospho-tau levels were elevated (Perrone et al., 2020).

Biological Effect

As described above, this variant has been associated with reduced CSF levels of Aβ42 and Aβ43, and a reduced Aβ42/Aβ40 ratio in one carrier (Perrone et al., 2020). Moreover, several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted it is damaging (Xiao et al., 2021). 

This variant has been classified as definitely pathogenic following the guidelines of Guerreiro et al. 2010 (Lanoiselée et al., 2017), deleterious following modified guidelines from Richards et al., 2015 (Koriath et al., 2018), and likely pathogenic following Richards et al., 2015 guidelines (Xiao et al., 2021).


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.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. R269H: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


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.


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: 28 Feb 2022


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Paper Citations

  1. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  2. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.
  3. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  4. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  5. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  6. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
  7. . Cerebral microbleeds in familial Alzheimer's disease. Brain. 2011 Jun 17; PubMed.
  8. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  9. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  10. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  11. . 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.
  12. . 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.
  13. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. ExAC v.10, Oct 2020

Further Reading


  1. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  2. . The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.

Protein Diagram

Primary Papers

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.

Other mutations at this position


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