ClinVar Genomic variation as it relates to human health
NM_000484.4(APP):c.2080G>A (p.Asp694Asn)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000484.4(APP):c.2080G>A (p.Asp694Asn)
Variation ID: 18101 Accession: VCV000018101.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q21.3 21: 25891853 (GRCh38) [ NCBI UCSC ] 21: 27264165 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Apr 15, 2024 Aug 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000484.4:c.2080G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000475.1:p.Asp694Asn missense NM_001136016.3:c.2008G>A NP_001129488.1:p.Asp670Asn missense NM_001136129.3:c.1687G>A NP_001129601.1:p.Asp563Asn missense NM_001136130.3:c.1912G>A NP_001129602.1:p.Asp638Asn missense NM_001136131.3:c.1750G>A NP_001129603.1:p.Asp584Asn missense NM_001204301.2:c.2026G>A NP_001191230.1:p.Asp676Asn missense NM_001204302.2:c.1969G>A NP_001191231.1:p.Asp657Asn missense NM_001204303.2:c.1801G>A NP_001191232.1:p.Asp601Asn missense NM_001385253.1:c.1912G>A NP_001372182.1:p.Asp638Asn missense NM_201413.3:c.2023G>A NP_958816.1:p.Asp675Asn missense NM_201414.3:c.1855G>A NP_958817.1:p.Asp619Asn missense NC_000021.9:g.25891853C>T NC_000021.8:g.27264165C>T NG_007376.2:g.284276G>A P05067:p.Asp694Asn - Protein change
- D563N, D584N, D601N, D619N, D638N, D657N, D670N, D675N, D676N, D694N
- Other names
- N694D
- Canonical SPDI
- NC_000021.9:25891852:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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APP | No evidence available | Some evidence for dosage pathogenicity |
GRCh38 GRCh37 |
444 | 552 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Mar 25, 2003 | RCV000019729.30 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 1, 2021 | RCV000084564.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2022 | RCV000687111.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alzheimer disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000814663.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APP function (PMID: 11441013, 26402770). Algorithms … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APP function (PMID: 11441013, 26402770). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 18101). This missense change has been observed in individuals with cerebral amyloid angiopathy (CAA) (PMID: 20228223, 24878480, 26104569, 27000221, 27858710, 28350801). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 694 of the APP protein (p.Asp694Asn). (less)
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Pathogenic
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962410.12
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Mar 25, 2003)
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no assertion criteria provided
Method: literature only
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CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, IOWA VARIANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040027.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In 2 brothers from Iowa with autosomal dominant cerebroarterial amyloidosis (605714), Grabowski et al. (2001) identified a mutation in the APP gene, resulting in an … (more)
In 2 brothers from Iowa with autosomal dominant cerebroarterial amyloidosis (605714), Grabowski et al. (2001) identified a mutation in the APP gene, resulting in an asp694-to-asn (D694N) substitution. This corresponds to residue N23D of the beta-amyloid peptide. Neither brother had symptomatic hemorrhagic stroke. Neuropathologic examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of beta-amyloid-40 in plaques. Greenberg et al. (2003) identified the D694N mutation in 2 affected members of a Spanish family with autosomal dominant dementia, occipital calcifications, leukoencephalopathy, and hemorrhagic strokes (see 605714). (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116700.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_105
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. | Lanoiselée HM | PLoS medicine | 2017 | PMID: 28350801 |
APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review. | Sellal F | Journal of Alzheimer's disease : JAD | 2017 | PMID: 27858710 |
Iowa APP mutation-related hereditary cerebral amyloid angiopathy (CAA): A new family from Spain. | Zarranz JJ | Journal of the neurological sciences | 2016 | PMID: 27000221 |
Modeling the Aggregation Propensity and Toxicity of Amyloid-β Variants. | Tiwari MK | Journal of Alzheimer's disease : JAD | 2015 | PMID: 26402770 |
Iowa-type hereditary cerebral amyloid angiopathy in a Polish family. | Iwanowski P | Journal of the neurological sciences | 2015 | PMID: 26104569 |
Familial cerebral amyloid angiopathy due to the Iowa mutation in an Irish family. | Mok T | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2014 | PMID: 24878480 |
Iowa variant of familial Alzheimer's disease: accumulation of posttranslationally modified AbetaD23N in parenchymal and cerebrovascular amyloid deposits. | Tomidokoro Y | The American journal of pathology | 2010 | PMID: 20228223 |
Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. | Greenberg SM | Neurology | 2003 | PMID: 12654973 |
Pathogenic effects of D23N Iowa mutant amyloid beta -protein. | Van Nostrand WE | The Journal of biological chemistry | 2001 | PMID: 11441013 |
Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. | Grabowski TJ | Annals of neurology | 2001 | PMID: 11409420 |
Text-mined citations for rs63749810 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.