Mutations
PSEN1 L226R
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Overview
Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity
Criteria: PM1, PM2, PM5, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659480 T>G
dbSNP ID: rs63749961
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: CTC to CGC
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 7
Findings
This variant was first reported in a case of familial early onset Alzheimer's disease in the U.S. (Coleman et al., 2004). It was subsequently found in a man from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). This carrier had AD with an age at onset of 44 years and a family history of the disease. He suffered from memory impairment, as well as from mental and behavioral changes. He had an APOE 3/4 genotype.
This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).
Neuropathology
In one individual, neuropathology was found to be consistent with AD, including numerous neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex (Coleman et al., 2004).
Biological Effect
Although the biological effects of this mutation is unknown, its location was noted as consistent with the helical alignment of pathogenic mutations in transmembrane domain 5 (Coleman et al., 2004).
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).
Pathogenicity
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.
PM1-M
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2-M
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.
PM5-M
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP2-P
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
PP3-P
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: 22 Feb 2022
References
Paper Citations
- Coleman P, Kurlan R, Crook R, Werner J, Hardy J. A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.
- Jiao B, Liu H, Guo L, Xiao X, Liao X, Zhou Y, Weng L, Zhou L, Wang X, Jiang Y, Yang Q, Zhu Y, Zhou L, Zhang W, Wang J, Yan X, Li J, Tang B, Shen L. The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
- Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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
Further Reading
Papers
- Ma L, Zhang J, Shi Y, Wang W, Ren Z, Xia M, Zhang Y, Yang M. Gene mutations in a Han Chinese Alzheimer's disease cohort. Brain Behav. 2019 Jan;9(1):e01180. Epub 2018 Dec 14 PubMed.
Protein Diagram
Primary Papers
- Coleman P, Kurlan R, Crook R, Werner J, Hardy J. A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.
Other mutations at this position
Alzpedia
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