Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004595171 | SCV005085931 | uncertain significance | Developmental and epileptic encephalopathy, 78 | 2023-12-21 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies on several missense variants have shown a significant reduction in GABA-induced current amplitudes and reduced protein levels and expression at the cell surface suggesting loss of function. However, dominant negative has not been ruled out and another study suggested the variant channels may be trapped in the open state, which could indicate a gain of function mechanism (PMIDs: 29961870, 31032849). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in an alternative transcript. This variant is coding in the ClinVar predominant and MANE select transcript, and in the two transcripts with the highest expression in GTEx. However, it is non-coding in three alternative transcripts, and the reported pathogenic or likely pathogenic variants in this gene are coding in all transcripts (ClinVar, PMIDs: 29961870, 31032849). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0708 - Other NMD-predicted variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. Three NMD-predicted variants are present in ClinVar. One is classified as pathogenic, while the other two are classified as VUS. One VUS was observed as de novo. (I) 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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |