Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3, BS2, BS3
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr21:25954593 G>A
Position: (GRCh37/hg19):Chr21:27326907 G>A
dbSNP ID: rs199586073
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTT to ATT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 13

Findings

This variant in APP 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 detected in one Caucasian control individual who was at least 60 years old at death. Further clinical details were not available. APOE genotype was ε3/ε3 (Sassi et al., 2014).

Of note, the variant was also present in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, with an allele count of one in a total of 954 alleles (HEX, Oct 2021). One European heterozygous carrier of this variant was reported in the gnomAD database (version 2.1.1, Oct 2021).

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and slightly less Aβ40 compared with cells expressing wild-type APP. The Aβ42/Aβ40 ratio was similar to controls (Hsu et al., 2020). Although Sassi and colleagues reported a "tolerated" prediction based on in silico analysis, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). The variant was classified as "benign" (Sassi et al., 2014) and "not pathogenic" (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because there are no reported carriers with AD and the variant is very rare, or absent, from gnomAD.

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

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

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.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

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

Last Updated: 15 Mar 2022

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References

Paper Citations

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.
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.

Mutations

APP V562I

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