ClinVar Genomic variation as it relates to human health
NM_002253.4(KDR):c.1615G>A (p.Gly539Arg)
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_002253.4(KDR):c.1615G>A (p.Gly539Arg)
Variation ID: 134605 Accession: VCV000134605.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q12 4: 55105862 (GRCh38) [ NCBI UCSC ] 4: 55972029 (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 Jun 9, 2014 Apr 15, 2024 Jan 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002253.4:c.1615G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002244.1:p.Gly539Arg missense NC_000004.12:g.55105862C>T NC_000004.11:g.55972029C>T NG_012004.1:g.24734G>A LRG_1198:g.24734G>A LRG_1198t1:c.1615G>A LRG_1198p1:p.Gly539Arg P35968:p.Gly539Arg - Protein change
- G539R
- Other names
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- Canonical SPDI
- NC_000004.12:55105861: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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0.00040 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00150
The Genome Aggregation Database (gnomAD), exomes 0.00151
Exome Aggregation Consortium (ExAC) 0.00161
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00161
Trans-Omics for Precision Medicine (TOPMed) 0.00170
1000 Genomes Project 0.00040
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
Help
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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KDR | - | - |
GRCh38 GRCh37 |
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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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not provided (1) |
no classification provided
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Sep 19, 2013 | RCV000121296.1 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2023 | RCV000862412.9 |
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
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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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Likely benign
(Dec 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001002919.2
First in ClinVar: Dec 17, 2019 Last updated: May 04, 2020 |
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Likely benign
(Jan 01, 2023)
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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: SCV004150675.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
KDR: BP4, BS1
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548817.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The KDR p.G539R variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The p.G539 variant … (more)
The KDR p.G539R variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The p.G539 variant was identified in control databases in 426 of 282734 chromosomes (1 homozygous) at a frequency of 0.001507 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 362 of 129064 chromosomes (freq: 0.002805), Other in 15 of 7218 chromosomes (freq: 0.002078), Latino in 23 of 35438 chromosomes (freq: 0.000649), South Asian in 10 of 30616 chromosomes (freq: 0.000327), African in 8 of 24958 chromosomes (freq: 0.000321), European (Finnish) in 6 of 25124 chromosomes (freq: 0.000239) and Ashkenazi Jewish in 2 of 10364 chromosomes (freq: 0.000193); it was not observed in the East Asian population. The variant was also identified in dbSNP (ID: rs55716939), ClinVar (one submission from ITMI in 2017, not classified) and Cosmic (confirmed somatically in stomach tissue—adenocarcinoma). The p.G539R variant was identified at an allele frequency of 0.0007 in a cohort of 681 healthy adults and 0.0015 among those of European descent (Bodian_2014_PMID: 24728327). The p.G539R variant was identified in liver tissue of a female with cancer of unknown primary origin, though it was not found to be a driver mutation (Pannuti_2018_PMID: 29570743). In an analysis of normal and tumor tissue from 210 cancers, p.G539R was identified twice in germline (Greenman_2007_PMID: 17344846). The p.G539R variant was also identified in the Geno2MP database in 33 individuals affected with a broad range of disorders and 24 relatives of affected individuals. The p.G539R variant lies within the Ig-like C2-type domain 5 of the KDR protein and one functional study found that p.G539R demonstrated greater activity than the WT counterpart (Egan_2017_PMID: 30761385). The p.G538R variant is predicted to lead to gain of KDR protein function and may play a role in oncogenesis (Egan_2017_PMID: 30761385). The p.Gly539 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085467.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs55716939 ...
HelpRecord last updated Apr 15, 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.