ClinVar Miner

Submissions for variant NM_004975.4(KCNB1):c.1237G>A (p.Val413Ile)

dbSNP: rs1984243311
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001262293 SCV001440107 likely pathogenic Developmental and epileptic encephalopathy, 26 2019-01-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001262293 SCV001490864 pathogenic Developmental and epileptic encephalopathy, 26 2022-09-13 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 413 of the KCNB1 protein (p.Val413Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 982681). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine RCV001262293 SCV002761296 likely pathogenic Developmental and epileptic encephalopathy, 26 2022-02-03 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001262293 SCV004847208 pathogenic Developmental and epileptic encephalopathy, 26 2023-08-25 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV001262293 SCV005374783 uncertain significance Developmental and epileptic encephalopathy, 26 criteria provided, single submitter clinical testing The observed missense c.1237G>A (p.Val413Ile) variant in KCNB1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val413Ile variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic/ Likely Pathogenic, however independent assessment is unavailble. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Val413Ile in KCNB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 413 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. However, additional literature and functional evidence will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

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