Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PM2, PP3, BS2, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25954663 T>C
Position: (GRCh37/hg19):Chr21:27326977 T>C
dbSNP ID: rs45537238
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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.

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Al-Sarraj S, Niblock M, Gallo JM, Adnan J, Killick R, Brown KS, Medway C, Lord J, Turton J, Bras J, Alzheimer's Research UK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. 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.e1-2881.e6. Epub 2014 Jun 16 PubMed.
2. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
3. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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