ClinVar

Description

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.