Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25911791 C>T
Position: (GRCh37/hg19):Chr21:27284103 C>T
dbSNP ID: NA
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 14

Findings

This variant was one of several rare polymorphisms detected by exome sequencing in a British cohort composed of 47 unrelated early onset Alzheimer’s disease cases and 179 elderly controls free of AD pathology. It was detected in one individual with autopsy-confirmed AD with onset at age 65. Further clinical details were not available. The variant was absent in control subjects (Sassi et al., 2014).

This variant was present in the gnomAD variant database at a frequency of 0.00001989 with an allele count of five (v2.1.1, Oct 2021). All carriers were heterozygotes, most of European (non-FInnish) descent.

Neuropathology

One reported carrier of the P620L variant had autopsy-confirmed AD. Further details have not been reported (Sassi et al., 2014).

Biological Effect

An assessment of secreted Aβ40 and Aβ42 in mouse neuroblastoma N2A cells expressing this variant revealed increased secretion of both peptides, with the Aβ42/Aβ40 ratio being similar to that of controls (Hsu et al., 2020).In silico analysis by Sassi and colleagues predicted the variant is "tolerated," but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). Sassi et al. considered the variant was most likely a rare, benign polymorphism in APP because it occurs outside of exons 16 and 17, where all pathogenic mutations known at that time were located (Sassi et al., 2014). However, taking into account more recent data, including the functional observations described above, Hsu and colleagues classified it as probably 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.

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-P

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. P620L: Five carriers in gnomAD, most of European 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

Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Mann D, Snowden J, Neary D, Harris J, Bras J, ARUK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 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 P620L

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