Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659443 C>T
dbSNP ID: rs63751003
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: CAC to TAC


This mutation was detected in a French family (Alz 178) with at least five family members affected by early onset Alzheimer’s disease. Onset in this family occurred at 37 to 45 years of age. Inheritance was reported as autosomal dominant, but details of the segregation with disease were not reported (Raux et al., 2005).  

This mutation was later reported in an Iranian patient with a positive family history of dementia. The family, known as DEM12, had at least seven members affected by dementia, with a notably variable clinical phenotype. The proband developed symptom onset at the age of 51, starting with apathy and depression. Progressive memory impairment followed, along with disorientation to time and space, non-fluent aphasia, and myoclonic jerks. Five years after onset he was severely demented with visual hallucinations and stereotypic behavior. The clinical phenotype in this family was variable. The proband's mother was alive at the time of the report, living with frontotemporal dementia at the age of 81. The proband's aunt and two cousins were affected by Parkinson's disease with dementia, an uncle had dementia, and a grandfather had AD. Segregation of H214Y with disease could not be determined due to lack of DNA from family members (Lohmann et al., 2012).


Unknown. Imaging of the Iranian proband at age 52 showed global cortical atrophy with marked frontotemporal atrophy and white-matter lesions (Lohmann et al., 2012).

Biological Effect

Unknown. In silico this mutation is predicted possibly damaging by PolyPhen-2. It has been classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012).


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Paper Citations

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  3. . 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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Primary Papers

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.

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