ClinVar Genomic variation as it relates to human health
NM_000484.4(APP):c.2149G>T (p.Val717Phe)
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.2149G>T (p.Val717Phe)
Variation ID: 18089 Accession: VCV000018089.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q21.3 21: 25891784 (GRCh38) [ NCBI UCSC ] 21: 27264096 (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 Dec 7, 2017 Mar 10, 2024 Jul 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000484.4:c.2149G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000475.1:p.Val717Phe missense NM_001136016.3:c.2077G>T NP_001129488.1:p.Val693Phe missense NM_001136129.3:c.1756G>T NP_001129601.1:p.Val586Phe missense NM_001136130.3:c.1981G>T NP_001129602.1:p.Val661Phe missense NM_001136131.3:c.1819G>T NP_001129603.1:p.Val607Phe missense NM_001204301.2:c.2095G>T NP_001191230.1:p.Val699Phe missense NM_001204302.2:c.2038G>T NP_001191231.1:p.Val680Phe missense NM_001204303.2:c.1870G>T NP_001191232.1:p.Val624Phe missense NM_001385253.1:c.1981G>T NP_001372182.1:p.Val661Phe missense NM_201413.3:c.2092G>T NP_958816.1:p.Val698Phe missense NM_201414.3:c.1924G>T NP_958817.1:p.Val642Phe missense NC_000021.9:g.25891784C>A NC_000021.8:g.27264096C>A NG_007376.2:g.284345G>T P05067:p.Val717Phe - Protein change
- V717F, V624F, V661F, V693F, V586F, V607F, V642F, V680F, V698F, V699F
- Other names
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- Canonical SPDI
- NC_000021.9:25891783:C:A
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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
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
445 | 556 |
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
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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) |
criteria provided, single submitter
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Nov 3, 2021 | RCV000815476.6 | |
Pathogenic (2) |
criteria provided, single submitter
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Jul 26, 2023 | RCV000019715.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2022 | RCV002054452.12 |
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
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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
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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
(Jan 01, 2022)
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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: SCV002496698.11
First in ClinVar: Apr 08, 2022 Last updated: Mar 10, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Alzheimer disease type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV004045802.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Depression (present) , Alzheimer disease (present) , Memory impairment (present)
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Pathogenic
(Nov 03, 2021)
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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: SCV000955932.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 18089). This variant is also known as Val642Phe. This missense change has been observed in individuals with early-onset Alzheimer's disease (PMID: 1925564, 15776278). 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 valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 717 of the APP protein (p.Val717Phe). Experimental studies have shown that this missense change affects APP function (PMID: 7806491, 7845465, 8191290, 11528419, 12707272, 20452985). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 21, 1999)
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no assertion criteria provided
Method: literature only
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ALZHEIMER DISEASE, FAMILIAL, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040013.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2017 |
Comment on evidence:
In affected members of a large Indiana kindred with autopsy-proven Alzheimer disease (104300), Murrell et al. (1991) identified a G-to-T transversion in the APP gene, … (more)
In affected members of a large Indiana kindred with autopsy-proven Alzheimer disease (104300), Murrell et al. (1991) identified a G-to-T transversion in the APP gene, resulting in a val717-to-phe (V717F) substitution. The substitution is 2 residues beyond the carboxyl terminus of the beta-amyloid peptide subunit isolated from amyloid fibrils. See also V717I (104760.0002) and V717G (104760.0004). Zeldenrust et al. (1993) identified the V717F substitution in 9 of 34 at-risk members of the original Indiana kindred reported by Murrell et al. (1991). Games et al. (1995) found that brains of transgenic mice overexpressing the V717F mutant protein showed typical pathologic findings of AD, including numerous extracellular thioflavine S-positive A-beta deposits, neuritic plaques, synaptic loss, astrocytosis, and microgliosis. Bales et al. (1999) quantified the amount of amyloid beta-peptide immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human APP mutation, with zero, 1, or 2 mouse ApoE (107741) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of V717F heterozygous mice that were ApoE -/- as old as 22 months of age, whereas age-matched V717F heterozygous animals which were either ApoE +/- or ApoE +/+ displayed abundant amyloid deposition. The amount of A-beta immunoreactivity in the hippocampus was also markedly reduced in an ApoE gene dose-dependent manner, and no A-beta immunoreactivity was detected in the cerebral cortex of V717F heterozygous mice that were ApoE -/- at any of the time points examined. Because the absence of ApoE altered neither the transcription nor the translation of the APP(V717F) transgene nor its processing to A-beta peptide(s), Bales et al. (1999) postulated that ApoE promotes both the deposition and fibrillization of A-beta, ultimately affecting clearance of protease-resistant A-beta/ApoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathologic hallmarks of Alzheimer disease. DeMattos et al. (2004) generated transgenic mice with the V717F mutation that were also null for ApoE, ApoJ (185430), or null for both Apo genes. The double Apo-knockout mice showed early-onset beta-amyloid deposition beginning at 6 months of age and a marked increase in amyloid deposition compared to the other mice. The amyloid plaques were compact and diffuse, were thioflavine S-positive indicating true fibrillar amyloid, and were distributed throughout the hippocampus and some parts of the cortex, contributing to neuritic plaques. The findings suggested that ApoE and ApoJ are not required for amyloid fibril formation. The double Apo knockout mice also had increased levels of intracellular soluble beta-amyloid compared to the other mice. Insoluble beta-42 was similar to the ApoE-null mice, suggesting that ApoE has a selective effect on beta-42. As APP is produced and secreted by neurons in the CNS, and apoE and apoJ are produced and secreted primarily by astrocytes in the CNS, the interaction between the apolipoproteins and beta-amyloid must occur in the interstitial fluid of the brain, an extracellular compartment that is continuous with the CSF. DeMattos et al. (2004) found that ApoE-null and ApoE/ApoJ-null mice had increased levels of beta-amyloid in the CSF and interstitial space, suggesting that ApoE, and perhaps ApoJ, play a role in regulating extracellular CNS beta-amyloid clearance independent of beta-amyloid synthesis. The data suggested that, in the mouse, ApoE and ApoJ cooperatively suppress beta-amyloid deposition. (less)
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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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Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif. | Munter LM | The Journal of biological chemistry | 2010 | PMID: 20452985 |
Novel mutations and repeated findings of mutations in familial Alzheimer disease. | Finckh U | Neurogenetics | 2005 | PMID: 15776278 |
Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. | Sato T | The Journal of biological chemistry | 2003 | PMID: 12707272 |
Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. | DeMattos RB | Science (New York, N.Y.) | 2002 | PMID: 11910111 |
The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. | Nilsberth C | Nature neuroscience | 2001 | PMID: 11528419 |
Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. | Bales KR | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 10611368 |
Familial Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of A beta 42(43). | Maruyama K | Biochemical and biophysical research communications | 1996 | PMID: 8886002 |
Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. | Games D | Nature | 1995 | PMID: 7845465 |
An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. | Suzuki N | Science (New York, N.Y.) | 1994 | PMID: 8191290 |
APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1-42/43 and a beta 1-40) in familial Alzheimer's disease brain. | Tamaoka A | The Journal of biological chemistry | 1994 | PMID: 7806491 |
RFLP analysis for APP 717 mutations associated with Alzheimer's disease. | Zeldenrust SR | Journal of medical genetics | 1993 | PMID: 7686976 |
A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. | Murrell J | Science (New York, N.Y.) | 1991 | PMID: 1925564 |
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Text-mined citations for rs63750264 ...
HelpRecord last updated Mar 11, 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.