Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Benign
ACMG/AMP Pathogenicity Criteria: PP4, BS1, BS2, BP4
Clinical Phenotype: Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
Position: Chr21:27253609 A>G
dbSNP ID: rs187940037
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Genomic Region: Exon 18, 3' UTR

Findings

This variant in the 3' UTR of APP was found in two out of 90 cases with cerebral amyloid angiopathy (CAA) (Nicolas et al., 2015). It is thought to be a rare benign polymorphism because it has also been found in controls, including in a handful of samples from the 1000 Genomes Project (4/1094). It was also reported in the gnomAD variant database at a frequency of 0.002261 with 71 allele counts (v2.1.1, Oct 2021). All carriers were heterozygotes, most with European (non-FInnish) ancestry.

Of the two mutation carriers with CAA, one experienced symptoms at age 73, including focal subarachnoid hemorrhage, cortical and juxtacortical microbleeds and white-matter hyperintensities. This individual did not have a family history of CAA. APOE genotype was ε3/ε4. The other patient developed symptoms at age 53. Clinical findings included two lobar intracerebral hemorrhages and cortical and juxtacortical microbleeds. APOE genotype was ε4/ε4. The patient’s mother presented with intracerebral hemorrhage at age 83.

Note, this variant is named according to its position in the 3' UTR.

Neuropathology

Unknown. At least two mutation carriers had hemorrhages and microbleeds consistent with CAA. However, this variant has also been detected in control samples.

Biological Effect

The biological effect of this variant is unknown. Of note, its PHRED-scaled CADD score, which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Oct 2021).

Pathogenicity

Cerebral Amyloid Angiopathy : Benign

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

PP4-P

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. c.*372 A>G: Most carriers are of European descent.

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.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 20.

	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

Nicolas G, Wallon D, Goupil C, Richard AC, Pottier C, Dorval V, Sarov-Rivière M, Riant F, Hervé D, Amouyel P, Guerchet M, Ndamba-Bandzouzi B, Mbelesso P, Dartigues JF, Lambert JC, Preux PM, Frebourg T, Campion D, Hannequin D, Tournier-Lasserve E, Hébert SS, Rovelet-Lecrux A. Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy. Eur J Hum Genet. 2015 Apr 1; PubMed.

Mutations

APP c.*372 A>G

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