Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3, BS4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25897607 A>G
Position: (GRCh37/hg19):Chr21:27269919 A>G
dbSNP ID: rs63749953
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAT to CGT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This mutation was detected in one of two siblings in an English family known as "Family 209." The pathogenicity of the H677R variant is unclear because only one sibling carried the mutation, but both had neuropathologically confirmed Alzheimer's disease. Neither sibling had any known mutations in PSEN1 or PSEN2, and neither carried the APOE ε4 allele. Information is limited about the previous generation of this family. It is possible that the H677R variant is an autosomal-dominant pathogenic mutation, with disease in the noncarrier sibling due to a sporadic form. Alternatively, H677R may be a benign polymorphism not associated with disease, and both siblings were affected by sporadic AD. H677R was absent in 100 healthy, unrelated controls (Janssen et al., 2003).

A single heterozygote carrier in the European (non-Finnish) population was reported in the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology

One mutation carrier had neuropathologically confirmed AD. A noncarrier sibling also had neuropathologically confirmed AD (Janssen et al., 2003).

Biological Effect

The H677R mutation causes an amino acid change within the Aβ region of APP, specifically altering the amino acid at position 6 of Aβ (H6R). The mutation does not affect Aβ production (Hori et al., 2007), but does alter the assembly kinetics of Aβ. Mutant Aβ peptides display accelerated secondary structure transitions and an increased propensity to form relatively large oligomers. The oligomers are also more efficient nucleators of fibril formation, and are significantly more cytotoxic than wild-type peptides (Ono et al., 2010).

Moreover, a structural modeling study predicted that the H6R Aβ peptide partitions into the membrane more than wild type Aβ (Kim and Bezprozvanny, 2023). This is expected to disrupt the normal function of these peptides in the endosomal lumen where they have been proposed to play important roles in synaptic and neuronal function.

This variant's PHRED-scaled CADD score was above 20, suggesting a damaging effect (CADD v1.6, 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.

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.

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.

BS4-S

Lack of segregation in affected members of a family.

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

Last Updated: 05 Apr 2023

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References

Paper Citations

Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
Hori Y, Hashimoto T, Wakutani Y, Urakami K, Nakashima K, Condron MM, Tsubuki S, Saido TC, Teplow DB, Iwatsubo T. The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Abeta fibril formation without increasing protofibril formation. J Biol Chem. 2007 Feb 16;282(7):4916-23. PubMed.
Ono K, Condron MM, Teplow DB. Effects of the English (H6R) and Tottori (D7N) familial Alzheimer disease mutations on amyloid beta-protein assembly and toxicity. J Biol Chem. 2010 Jul 23;285(30):23186-97. PubMed.
Kim M, Bezprozvanny I. Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease. Int J Mol Sci. 2023 Jan 20;24(3) PubMed.

Mutations

APP H677R (English)

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