Mutations

APP c.*18 C>T

Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP4, BS1, BP4
Clinical Phenotype: Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
Position: Chr21:27253963 C>T
dbSNP ID: rs201729239
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 one out of 90 cases with cerebral amyloid angiopathy (CAA) (Nicolas et al., 2015). The patient was diagnosed with probable CAA at the age of 58 based on clinical findings and imaging. He presented with an ischemic stroke in his right middle cerebral artery. One month later he developed hematomas in his right temporal and parietal lobes. MRI showed numerous cortical microbleeds along with white-matter hyperintensities. Five years later he had another spontaneous right lobar hematoma. He had no family history of CAA. No additional sequence abnormalities at the APP locus were observed. His APOE genotype was ε2/ε3.

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

Seven heterozygote carriers were reported in the gnomAD variant database (v2.1.1, Oct 2021), six of whom were of European (non-Finnish) descent.

Neuropathology

Unknown. Imaging showed an ischemic stroke in the right middle cerebral artery. Later he developed hematomas in his right temporal and parietal lobes. MRI showed numerous cortical microbleeds along with white-matter hyperintensities.

Biological Effect

The biological effect of this variant is unknown. Its PHRED-scaled CADD score, which integrates diverse information in silico, was just shy of 20, a commonly used threshold  for predicting deleteriousness (CADD v.1.6, Oct 2021).

Pathogenicity

Cerebral Amyloid Angiopathy : Likely 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.*18 C>T: Most carriers are of European descent.

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

  1. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. 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.

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