Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891850 G>A
Position: (GRCh37/hg19):Chr21:27264162 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant was found in a targeted sequencing study of index cases from 148 unrelated families—each with at least two first-degree relatives who suffered from dementia—from mainland China (Gao et al., 2019). The carrier was 60 years old at symptom onset, and his APOE genotype was ε2/ε3. His family history was consistent with an autosomal-dominant pattern of inheritance, as his mother (age of onset 80 years), maternal grandfather, and a maternal aunt were also afflicted with dementia. Genotype information was not available from family members, precluding segregation analysis.

This variant was not found in 100 ethnically- and age-matched controls, nor was it found in the gnomAD database.

Biological Effect

The biological effect of the valine-to-methionine substitution has not been tested directly. The variant was predicted to be tolerated by SIFT and to be benign by PolyPhen-2, while Mutation Taster classified it as disease-causing. The valine residue at position 695 is conserved among species. The PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 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.

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.

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

Mutations

APP V695M

Quick Links

Overview

Findings

Biological Effect

Pathogenicity

Alzheimer's Disease : Not Classified*

PM1-M

PM2-M

PP2-P

PP3-P

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References

Paper Citations

Further Reading

Protein Diagram

Primary Papers

Other mutations at this position

Alzpedia