Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002028070 | SCV002317493 | likely pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2022-08-26 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1522201). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly271 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16691402; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KCNQ2 protein function. This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 271 of the KCNQ2 protein (p.Gly271Ser). |
| Victorian Clinical Genetics Services, |
RCV002272564 | SCV002557087 | pathogenic | Developmental and epileptic encephalopathy, 7 | 2023-02-03 | 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 and loss of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 7 (DEE; MIM#613720) and benign neonatal seizures, 1 (BFNE; MIM#121200), respectively (GeneReviews). There is currently no phenotypic correlation in terms of variant types or protein location (PMID: 31418850). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance however, this is only reported for patients with BNS (PMID: 25959266). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) in the pore domain (UniProt). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative changes at the same codon have been previously reported in four individuals, including one variant that was seen in 17 affected members of one family with neonatal onset seizures (PMID: 25960349, 33659638, 16691402). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |