Submissions for variant NM_004975.4(KCNB1):c.1246T>C (p.Phe416Leu)

dbSNP: rs1984242860

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001065353	SCV001230309	pathogenic	Developmental and epileptic encephalopathy, 26	2022-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 416 of the KCNB1 protein (p.Phe416Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 31600826). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 859281). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNB1 protein function. Experimental studies have shown that this missense change affects KCNB1 function (PMID: 31600826). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003319441	SCV004023587	pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced Kv2.1 channel expression and function (Kang et al., 2019; Yu et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Riva_2022_Abstract, 31682765, 31600826)
Kearney Laboratory, Northwestern University Feinberg School of Medicine	RCV003319441	SCV004024576	not provided	not provided		no assertion provided	in vitro