Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS4, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26000030 G>A
Position: (GRCh37/hg19):Chr21:27372345 G>A
dbSNP ID: rs768499633
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 7

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 V340M was identified in three affected family members and two of 10 unaffected members (ages were not reported). Association with AD was reported as significant using families and 498 unrelated controls in a joint linkage and family-based association analysis.

The variant was present in the gnomAD variant database at a frequency of 0.00001770, with five heterozygotes, most of European (non-Finnish) ancestry (v2.1.1, Feb 2022).

Neuropathology
Unknown.

Biological Effect
The biological effect of this variant is unknown. One study reported no effect on the Aβ42/Aβ40 ratio or Aβ42 levels, but the supporting data were not available (Hsu et al., 2020). In silico algorithms SIFT and Polyphen predicted it is probably damaging (Lee et al., 2014; Hsu et al., 2020), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, consistent with a deleterious effect (v6.1, Feb 2022). Hsu and colleagues classified this variant as not pathogenic (Hsu et al., 2020).

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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. V340M: Joint linkage and family-based association analysis indicated an association with AD.

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-P

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. V340M: The frequency of this variant is only slightly greater than expected for autosomal dominant disease, and statistical analyses suggested association with disease.

	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

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.
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 V340M

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