Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP1, BS1, BS2, BS3
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr21:25891639_25891634 ATACTT>------
Position: (GRCh37/hg19):Chr21:27263951_27263946 ATACTT>------
dbSNP ID: rs367709245
Coding/Non-Coding: Non-Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Genomic Region: Intron 17

Findings

This variant involves the deletion of six base pairs from intron 17 of the APP gene. The clinical significance of this deletion is unknown. It was first reported in 1992 in three people with AD and one cognitively healthy control (Kamino et al., 1992). Of the three affected mutation carriers, two were siblings in an FAD kindred, with onset at age 62 and 74. An unaffected sibling did not carry the mutation, suggesting segregation with disease. The third deletion carrier with AD developed symptoms at age 58 and was also considered to have familial AD, although the reported pedigree indicates just one additional affected individual, a sibling with onset at age 57 and an unknown mutation status. The deletion was also found in one out of 207 cognitively healthy controls.

This deletion variant has since been identified in Phase 3 of the 1000 Genomes Project. It was seen in one of 661 people of African ancestry and two of 346 people of Puerto Rican ancestry (1000 Genomes Project Consortium et al., 2012). In the gnomAD variant database, the variant was found at a frequency of 0.001466 with an allele count of 46 (gnomAD v2.1.1, Oct 2021). Most of these carriers were of European ancestry.

Most recently, a study from the United Kingdom reported this deletion in five out of 451 individuals with sporadic early onset AD, two out of 584 individuals with late-onset AD, and two out of 528 controls. All carriers were heterozygous for the deletion. One of the AD cases had neuropathologically confirmed AD; the others were diagnosed with probable AD based on clinical criteria. The observed minor allele frequency (MAF) in the sporadic early onset AD cohort (0.006) was non-significantly elevated compared with the frequencies seen in late-onset AD (0.002) and controls (0.002). However, many more samples would be needed to achieve sufficient power to determine if there is a real association between this rare variant and disease (Barber et al., 2015).

Neuropathology

Unknown. At least one deletion carrier with sporadic early onset AD had neuropathology consistent with AD at autopsy (Barber et al., 2015).

Biological Effect

This variant involves a hexanucleotide deletion (AAGTAT) from intron 17 of APP. The deletion is located 83 base pairs downstream of exon 17. Experiments in transfected cells did not find evidence that the deletion altered splicing of exon 17 in APP (Barber et al., 2015). Note, the APP IVS17 83-88delAAGTAT variant is named in reference to the transcript, which is transcribed from the reverse strand. However, the forward strand is the standard reference for the genomic sequence, thus the hexanucleotide deletion is written as the inverse of the complementary nucleotides (i.e., ATACTT).

Pathogenicity

Alzheimer's Disease : Benign*

*This variant's frequency was elevated in a sporadic early onset AD cohort compared with controls, but the difference did not reach statistical significance.

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

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References

Paper Citations

1. Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, Anderson L, O'dahl S, Nemens E, White JA. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992 Nov;51(5):998-1014. PubMed.
2. , Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012 Nov 1;491(7422):56-65. PubMed.
3. Barber IS, García-Cárdenas JM, Sakdapanichkul C, Deacon C, Zapata Erazo G, Guerreiro R, Bras J, Hernandez D, Singleton A, Guetta-Baranes T, Braae A, Clement N, Patel T, Brookes K, Medway C, Chappell S, Mann DM, ARUK Consortium, Morgan K. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease. Neurobiol Aging. 2016 Mar;39:220.e1-7. Epub 2015 Dec 29 PubMed.

Further Reading

No Available Further Reading