Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001209556 | SCV001380996 | uncertain significance | Developmental and epileptic encephalopathy, 26 | 2023-07-18 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 940052). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 293 of the KCNB1 protein (p.Arg293Cys). 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 (PMID: 34490615). In at least one individual the variant was observed to be de novo. This missense change has been observed in at least one individual who was not affected with KCNB1-related conditions (Invitae). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| New York Genome Center | RCV001209556 | SCV002099418 | likely pathogenic | Developmental and epileptic encephalopathy, 26 | 2021-02-26 | criteria provided, single submitter | clinical testing | The de novo heterozygous missense c.877C>T (p.Arg293Cys) variant identified in the KCNB1 gene has not been reported in affected individuals in the literature. The variant is absent from gnomAD database suggesting it is not a common benign allele in the populations represented in that database. The variant affects a highly conserved residue and is predicted deleterious by multiple in silico tools [CADD score = 32, REVEL score =0.858]. Based on the available evidence, the de novo heterozygous missense c.877C>T (p.Arg293Cys) variant identified in the KCNB1 gene is reported as Likely Pathogenic. |
| Mendelics | RCV001209556 | SCV002516589 | pathogenic | Developmental and epileptic encephalopathy, 26 | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV001209556 | SCV002557759 | pathogenic | Developmental and epileptic encephalopathy, 26 | 2022-06-24 | criteria provided, single submitter | clinical testing | 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) 0600 - Variant is located in the annotated ion transport protein domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed as de novo in one individual and classified as likely pathogenic by a clinical laboratory in ClinVar. Another clinical laboratory in ClinVar classified this variant as a VUS. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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 |