Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP(all): 265/13006=2.03%
ClinVar Genomic variation as it relates to human health
NM_002253.4(KDR):c.1444T>C (p.Cys482Arg)
Germline
Classification
Help
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.
(6)
Help
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.
Likely benign
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002253.4(KDR):c.1444T>C (p.Cys482Arg)
Variation ID: 12318 Accession: VCV000012318.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q12 4: 55972946 (GRCh37) [ NCBI UCSC ] 4: 55106779 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 29, 2024 Jul 7, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002253.4:c.1444T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002244.1:p.Cys482Arg missense NC_000004.12:g.55106779A>G NC_000004.11:g.55972946A>G NG_012004.1:g.23817T>C LRG_1198:g.23817T>C LRG_1198t1:c.1444T>C LRG_1198p1:p.Cys482Arg P35968:p.Cys482Arg - Protein change
- C482R
- Other names
- -
- Canonical SPDI
- NC_000004.12:55106778:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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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0.00899 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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1000 Genomes Project 0.00899
1000 Genomes Project 30x 0.00968
Trans-Omics for Precision Medicine (TOPMed) 0.01926
Exome Aggregation Consortium (ExAC) 0.02231
The Genome Aggregation Database (gnomAD), exomes 0.02298
The Genome Aggregation Database (gnomAD) 0.02299
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| KDR | - | - |
GRCh38 GRCh37 |
134 | 157 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely benign (2) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV000013111.5 | |
| Likely benign (2) |
criteria provided, single submitter
|
Mar 28, 2016 | RCV000121295.5 | |
| Likely benign (2) |
criteria provided, single submitter
|
- | RCV001355593.4 |
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
Help
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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Likely benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Capillary infantile hemangioma
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015780.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
|
Likely benign
(Mar 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539466.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP(all): 265/13006=2.03% (less)
Method: Genome/Exome Filtration
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005257390.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550520.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The KDR p.Cys482Arg variant was identified in dbSNP (ID: rs34231037) as well as ClinVar (reported as likely benign by the Laboratory for Molecular Medicine, Partners … (more)
The KDR p.Cys482Arg variant was identified in dbSNP (ID: rs34231037) as well as ClinVar (reported as likely benign by the Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), Clinvitae, Cosmic (FATHMM prediction of pathogenic (score=0.99)), MutDB (classified as a polymorphism by SwissProt) and LOVD 3.0. The variant was identified in control databases in 6505 of 282288 chromosomes (95 homozygous) at a frequency of 0.023044 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 (Finnish) in 1202 of 25118 chromosomes (freq: 0.04785), European (non-Finnish) in 4106 of 128738 chromosomes (freq: 0.03189), Other in 179 of 7198 chromosomes (freq: 0.02487), Ashkenazi Jewish in 178 of 10354 chromosomes (freq: 0.01719), Latino in 486 of 35398 chromosomes (freq: 0.01373), South Asian in 209 of 30610 chromosomes (freq: 0.006828) and African in 145 of 24926 chromosomes (freq: 0.005817); it was not observed in the East Asian populations. The variant was identified in the literature where it was identified in a population of patients with Hemangioma at a frequency of 0.044, however it was also identified in a control population at a frequency of 0.041 (Jinnin_2008_18931684). The C482R variant was also found to be associated with soluble VEGFR2 levels and greater sensitivity and response to pazopanib (Maitland_2015_25411163), and was also associated with better sunitinib response (Apell√°niz-Ruiz_2017_28430711). The p.Cys482 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
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risk factor
(Nov 01, 2008)
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no assertion criteria provided
Method: literature only
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HEMANGIOMA, CAPILLARY INFANTILE, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033358.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2018 |
Comment on evidence:
In 2 unrelated patients with infantile hemangioma (602089), Jinnin et al. (2008) identified a germline T-to-C transition in the KDR gene, resulting in a cys482-to-arg … (more)
In 2 unrelated patients with infantile hemangioma (602089), Jinnin et al. (2008) identified a germline T-to-C transition in the KDR gene, resulting in a cys482-to-arg (C482R) substitution in the extracellular region. The same change was identified in 8 of 105 additional individuals with hemangioma and in 12 of 295 controls. Expression of FLT1 (165070) in hemangioma endothelial cells was markedly reduced, and KDR activity was increased, compared to controls. In normal endothelial cells, FLT1 transcription is dependent on NFAT (see, e.g., NFATC2; 600490) activation. Further studies indicated that low VEGFR1 expression in hemangioma cells was caused by reduced activity of a pathway involving ITGB1 (135630), TEM8 (ANTXR1; 606410), KDR, and NFAT. The KDR mutation was predicted to result in loss of function and disruption of the normal association of these molecules, leading to an increased risk for development of hemangioma. (less)
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|
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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
|
ITMI
Accession: SCV000085466.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
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
|
Comment:
Comment:
The KDR p.Cys482Arg variant was identified in dbSNP (ID: rs34231037) as well as ClinVar (reported as likely benign by the Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), Clinvitae, Cosmic (FATHMM prediction of pathogenic (score=0.99)), MutDB (classified as a polymorphism by SwissProt) and LOVD 3.0. The variant was identified in control databases in 6505 of 282288 chromosomes (95 homozygous) at a frequency of 0.023044 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 (Finnish) in 1202 of 25118 chromosomes (freq: 0.04785), European (non-Finnish) in 4106 of 128738 chromosomes (freq: 0.03189), Other in 179 of 7198 chromosomes (freq: 0.02487), Ashkenazi Jewish in 178 of 10354 chromosomes (freq: 0.01719), Latino in 486 of 35398 chromosomes (freq: 0.01373), South Asian in 209 of 30610 chromosomes (freq: 0.006828) and African in 145 of 24926 chromosomes (freq: 0.005817); it was not observed in the East Asian populations. The variant was identified in the literature where it was identified in a population of patients with Hemangioma at a frequency of 0.044, however it was also identified in a control population at a frequency of 0.041 (Jinnin_2008_18931684). The C482R variant was also found to be associated with soluble VEGFR2 levels and greater sensitivity and response to pazopanib (Maitland_2015_25411163), and was also associated with better sunitinib response (Apell√°niz-Ruiz_2017_28430711). The p.Cys482 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
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. |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP(all): 265/13006=2.03%
Comment:
The KDR p.Cys482Arg variant was identified in dbSNP (ID: rs34231037) as well as ClinVar (reported as likely benign by the Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), Clinvitae, Cosmic (FATHMM prediction of pathogenic (score=0.99)), MutDB (classified as a polymorphism by SwissProt) and LOVD 3.0. The variant was identified in control databases in 6505 of 282288 chromosomes (95 homozygous) at a frequency of 0.023044 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 (Finnish) in 1202 of 25118 chromosomes (freq: 0.04785), European (non-Finnish) in 4106 of 128738 chromosomes (freq: 0.03189), Other in 179 of 7198 chromosomes (freq: 0.02487), Ashkenazi Jewish in 178 of 10354 chromosomes (freq: 0.01719), Latino in 486 of 35398 chromosomes (freq: 0.01373), South Asian in 209 of 30610 chromosomes (freq: 0.006828) and African in 145 of 24926 chromosomes (freq: 0.005817); it was not observed in the East Asian populations. The variant was identified in the literature where it was identified in a population of patients with Hemangioma at a frequency of 0.044, however it was also identified in a control population at a frequency of 0.041 (Jinnin_2008_18931684). The C482R variant was also found to be associated with soluble VEGFR2 levels and greater sensitivity and response to pazopanib (Maitland_2015_25411163), and was also associated with better sunitinib response (Apell√°niz-Ruiz_2017_28430711). The p.Cys482 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. | Jinnin M | Nature medicine | 2008 | PMID: 18931684 |
Text-mined citations for rs34231037 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.