Mutations

APP Y538H

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27326977 T>C
dbSNP ID: rs45537238
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to CAT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 13

Findings

This variant was found in an exome sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls without significant neuropathology. The variant was found in a Caucasian individual diagnosed with AD at the age of 69. Death occurred at age 77. APOE genotype was ε3/ε4. Family history information was not reported. This variant was absent in the 179 controls screened (Sassi et al., 2014). However, it is present in the ExAC variant database at a frequency of 0.007396 (ExAC v.1, Aug 2020). It is also found at a frequency of 0.002 in HEX, a database of exome variants from nearly 500 people age 60 or older, who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death. 

Neuropathology

Unknown.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted approximately half the amount of both Aβ42 and Aβ40 as cells expressing wild-type PSEN1. The Aβ42/Aβ40 ratio was similar to controls (Hsu et al., 2020). 

The Y538H substitution was predicted to be possibly damaging by Polyphen in silico analysis and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). However, the variant is not within an APP region known to harbor pathogenic mutations and was classified as a "likely benign polymorphism" according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014). Hsu et al. classified the mutation as not pathogenic and possibly protective.

Last Updated: 13 Oct 2021

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References

Paper Citations

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 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.

Other Citations

  1. HEX

External Citations

  1. ExAC v.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.

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