Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26000152 C>T
Position: (GRCh37/hg19):Chr21:27372467 C>T
dbSNP ID: rs202074408
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 7

Findings

This APP variant was identified by whole-exome sequencing in one of 424 French people with early onset AD (Nicolas et al., 2015). Because it is located in exon 7, the P299L variant is considered unlikely to be pathogenic.

This variant was found in the gnomAD variant database at a frequency of 0.00001592, with an allele count of four which included two individuals of South Asian descent and two of European descent (gnomAD, v2.1.1, Oct 2021). 

Neuropathology

Unknown.

Biological Effects

The biological effects of this variant are unknown, but the PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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. Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard AC, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Maréchal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Sauvée M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.

External Citations

1. gnomAD, v2.1.1
2. CADD v.1.6

Further Reading

No Available Further Reading