Mutations

APP T297M

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26000158 C>T
Position: (GRCh37/hg19):Chr21:27372473 C>T
dbSNP ID: rs557227002
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 7

Findings

This variant was identified in a whole-exome sequencing study of Chinese Alzheimer’s cases with a family history consistent with autosomal-dominant inheritance (Jiang et al., 2019). The carrier was a 54-year-old man who began experiencing symptoms of cognitive decline and concentration deficits at age 50. His mother and elder brother had similar histories but were not genotyped. A carrier was also reported in a subsequent study of a Taiwanese cohort of patients with early onset dementia (Hsu et al., 2021).

The T297M variant was not found in the 1000 Genomes Project database or in 500 ethnically and age-matched controls (Jiang et al., 2019). However, this variant was found in gnomAD with an allele frequency of 1.84 X 10-4, with all but one carrier found among the South and East Asian populations (v2.1.1, searched 2020-10-14).

Biological Effect

The biological effect of the threonine-to-methionine substitution has not been tested directly yet. The T297M mutation is predicted to be damaging by PolyPhen-2 and deleterious by SIFT (Jiang et al., 2019).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  T297M: Most carriers are of Asian descent.

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

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References

Paper Citations

  1. Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  2. Hsu JL, Lin CH, Chen PL, Lin KJ, Chen TF. Genetic study of young-onset dementia using targeted gene panel sequencing in Taiwan. Am J Med Genet B Neuropsychiatr Genet. 2021 Mar;186(2):67-76. Epub 2021 Feb 13 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.

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