Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227083222 C>T
dbSNP ID: rs63750666
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACG to ATG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13


This mutation was first identified in a Spanish patient with a clinical picture typical of early onset Alzheimer's disease, with onset at age 45. Later in the course of the disease the proband developed myoclonus, grasping, and generalized epileptic seizures in addition to progressive cognitive and behavioral disturbances. The patient died at age 56. In addition to the proband and the proband's mother, one grandparent had received a diagnosis of AD. The mother died at age 75, following disease onset at age 64, and the grandparent died at age 70, following disease onset at age 60. Some family members also had a history of Tourette syndrome (Lleó et al 2002; Ezquerra et al., 2003).

The mutation was also detected in the proband's affected mother, an affected sibling, and a cognitively healthy sibling. The age of the unaffected carrier was not reported, however, although it was noted it was greater than that of the proband. The mutation was absent from 50 unrelated healthy controls and 80 unrelated AD patients.

The allele count and frequency of this variant in the gnomAD database were 9 and 0.0036 percent, respectively, and it was predicted by a subsequent study to have less than 10 percent penetrance (Koriath et al., 2018). Based on these data, Koriath and colleagues described the variant as "most likely benign" or causing an "only small increase in risk." Of note, five of the nine heterozygotes reported in gnomAD were of Latino/Admixed American ancestry (v2.1.1, Nov 2021).


Postmortem examination was not performed. Neuroimaging showed right frontotemporal hypoperfusion in the proband (Ezquerra et al., 2003).

Biological Effect

The biological effects of this variant are unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was 31, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Last Updated: 11 Nov 2021


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Paper Citations

  1. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.
  2. . A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Arch Neurol. 2003 Aug;60(8):1149-51. PubMed.
  3. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Arch Neurol. 2003 Aug;60(8):1149-51. PubMed.


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