ClinVar Miner

Submissions for variant NM_002253.4(KDR):c.2066C>T (p.Thr689Met)

gnomAD frequency: 0.00307  dbSNP: rs34038364
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000861134 SCV001001362 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
ITMI RCV000121297 SCV000085468 not provided not specified 2013-09-19 no assertion provided reference population
Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville. RCV000201301 SCV000222718 uncertain significance Hirschsprung disease, susceptibility to, 1 2015-04-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000861134 SCV001550185 likely benign not provided no assertion criteria provided clinical testing The KDR p.Thr689Met variant was not identified in the literature but was identified in dbSNP (ID: rs34038364), ClinVar (classified as uncertain significance by Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 916 of 282566 chromosomes (7 homozygous) at a frequency of 0.003242 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 370 of 25118 chromosomes (freq: 0.01473), Other in 40 of 7210 chromosomes (freq: 0.005548), European (non-Finnish) in 392 of 128968 chromosomes (freq: 0.00304), Latino in 92 of 35386 chromosomes (freq: 0.0026), African in 21 of 24964 chromosomes (freq: 0.000841) and Ashkenazi Jewish in 1 of 10360 chromosomes (freq: 0.000097), but was not observed in the East Asian or South Asian populations. The p.Thr689 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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