Mutations

APP S614G

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27284122 A>G
dbSNP ID: rs112263157
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGC to GGC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 14

Findings

This variant was reported in a study of families with four or more relatives presumed to have Alzheimer’s disease (AD), living in the Dominican Republic and Puerto Rico (Lee et al., 2014). Targeted resequencing of the exons in the APP, PSEN1, PSEN2, GRN, and MAPT genes of 183 individuals was performed. APP S614G was identified in one affected individual and in eight unrelated controls. It was also reported in the gnomAD variant database at a frequency of 0.001428, including 404 heterozygotes and 5 homozygotes (v2.1.1, Feb 2022). Most of these carriers were of African ancestry.

Neuropathology
Unknown.

Biological Effect
An assessment of secreted Aβ40 and Aβ42 in mouse neuroblastoma N2A cells expressing the S614G mutation revealed an increased Aβ42/Aβ40 ratio, with a decrease in Aβ40 and an increase in Aβ42 levels (Hsu et al., 2020). Although two in silico algorithms predicted it is benign (Polyphen) and tolerated (SIFT), the variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (v1.6, Feb 2022). Hsu and colleagues classified the variant as a risk factor.

Pathogenicity

Alzheimer's Disease : Uncertain Significance*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

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

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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.  S614G: Most carriers were of African ancestry.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 10 May 2022

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References

Paper Citations

  1. Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Williamson J, Nagy P, Mayeux R. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Williamson J, Nagy P, Mayeux R. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 PubMed.

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