Submissions for variant NM_004975.4(KCNB1):c.1106G>T (p.Trp369Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	RCV002466342	SCV002761297	likely pathogenic	Developmental and epileptic encephalopathy, 26	2022-02-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002466342	SCV003234965	pathogenic	Developmental and epileptic encephalopathy, 26	2024-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 369 of the KCNB1 protein (p.Trp369Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNB1-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1803045). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNB1 protein function with a positive predictive value of 95%. This variant disrupts the p.Trp369 amino acid residue in KCNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31513310, 31780880). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.