Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 26 (MIM#616056). However, the ultimate result of each mechanism is channel dysfunction (PMID: 31512327). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a cluster of pathogenic variants, S4 of the voltage-sensing domain (PMID: 26477325). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The alternative change to a histidine has been reported once as likely pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent de novo variant in individuals with developmental and epileptic encephalopathy (ClinVar, PMID: 26477325, 29264397, 28806457, 31513310). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using transfected Neuro2a cells showed that the variant disrupts sensitivity and cooperativity of the sensor (PMID: 26477325). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 15, 2021 | The de novo c.916C>T (p.Arg306Cys variant in exon 2 of 2 of KCNB1 has been reported in multiple affected individuals in the available literature [PMID: 26477325.; PMID: 27652284; PMID: 29264397; PMID: 31513310; PMID: 32469098]. It is also submitted multiple times in ClinVar database by independent clinical laboratories and classified as Pathogenic/Likely Pathogenic (VarID: 449693). This variant is absent in gnomAD suggesting it is not a common benign variant in the populations represented in this database. In silico predictors suggest this variant is Pathogenic (REVEL; score: 0.86) and damaging (SIFT; score: 0). Functional studies have shown this variant in the voltage sensor domain S4, disrupts sensitivity and cooperativity of the sensor and results in loss of voltage sensing [2]. Given this evidence the de novo c.916C>T (p.Arg306Cys) variant identified in the KCNB1 gene is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNB1 function (PMID: 26477325). 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. ClinVar contains an entry for this variant (Variation ID: 449693). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26477325, 28806457, 29264397). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 306 of the KCNB1 protein (p.Arg306Cys). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 22, 2022 | _x000D_ Criteria applied: PS2, PS4, PM1_SUP, PM2_SUP, PP2, PP3 - |