Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3, PP4
Clinical Phenotype: Cerebral Amyloid Angiopathy
Position: (GRCh38/hg38):Chr21:25891820 C>G
Position: (GRCh37/hg19):Chr21:27264132 C>G
dbSNP ID: rs63750921
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to GTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was first reported in a three-generation Italian family with autosomal-dominant, recurrent hemorrhagic stroke in the fifth to eighth decade of life (Obici et al., 2005). The proband and three affected cousins carried the mutation while an unaffected 74-year-old cousin did not, suggesting cosegregation of the mutation with disease.

A second instance of this mutation was reported in 2020 (Kozberg et al., 2020). At age 62, the carrier suffered multiple, large intracerebral hemorrhages over a four-month period, the last of which was fatal. Notably, except for brief periods immediately following each hemorrhage, her cognition remained intact. As in the original report of this mutation, there is a family history of hemorrhagic strokes in individuals in their 40s to 70s that is consistent with an autosomal dominant pattern of inheritance. Genetic information was not available from family members, precluding segregation analysis. This family is of English and Welsh ancestry and is not believed to be related to the Italian family described above.

This mutation is absent from the gnomAD variant database (V2.1.1, Oct 2021).

Neuropathology

Pathological examination of the Italian carrier revealed severe cerebral amyloid angiopathy with evidence of hemorrhages originating from affected vessels and cracking of the vessel walls, creating a “vessel-within-vessel” appearance. The amyloid deposition appeared to selectively affect vessel walls. There was no evidence of Aβ parenchymal deposits (either diffuse or neuritic plaques), nor were neurofibrillary tangles or dystrophic neurites observed (Obici et al., 2005).

Similar to the Italian carrier, the carrier described in 2020 exhibited severe CAA—most prominent in leptomeningeal vessels—but no parenchymal amyloid plaques or neurofibrillary tangles (Kozberg et al., 2020).

Biological Effect

A yeast cell-based assay to monitor Aβ aggregation revealed this substitution accelerates nucleation compared with the wildtype peptide (Seuma et al., 2022, suppl 3). Also of note, L705 lies within a cholesterol-binding site as determined by NMR resonance spectroscopy and site-directed mutagenesis (Barrett et al., 2012).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Cerebral Amyloid Angiopathy : Pathogenic*

*Although not AD, the condition associated with this variant is inherited in an autosomal dominant manner, so its pathogenicity was classified using the ACMG guidelines.

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.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP1-P

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. L705V: Although >3 affected carriers were reported, the wide range of age at onset weakens the value of the unaffected non-carrier as evidence for establishing cosegregation.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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.

PP4-P

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

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 07 Apr 2023

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References

Paper Citations

Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S, Arbustini E, Palladini G, Diegoli M, Genovese E, Ferrari G, Coverlizza S, Merlini G. A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005 Oct;58(4):639-44. PubMed.
Kozberg MG, van Veluw SJ, Frosch MP, Greenberg SM. Hereditary cerebral amyloid angiopathy, Piedmont-type mutation. Neurol Genet. 2020 Apr;6(2):e411. Epub 2020 Mar 13 PubMed.
Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. PubMed.
Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012 Jun 1;336(6085):1168-71. PubMed.

Mutations

APP L705V

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