Submissions for variant NM_002253.4(KDR):c.1444T>C (p.Cys482Arg)

gnomAD frequency: 0.02299  dbSNP: rs34231037

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121295	SCV000539466	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	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%
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000013111	SCV004015780	likely benign	Capillary infantile hemangioma	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001355593	SCV005257390	likely benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000013111	SCV000033358	risk factor	Capillary infantile hemangioma	2008-11-01	no assertion criteria provided	literature only
ITMI	RCV000121295	SCV000085466	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355593	SCV001550520	likely benign	not provided		no assertion criteria provided	clinical testing	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.