Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV001779368 | SCV002014705 | uncertain significance | Febrile seizures, familial, 8 | 2021-10-25 | criteria provided, single submitter | clinical testing | This variant is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.839, 3Cnet: 0.982, PP3). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Centre de Biologie Pathologie Génétique, |
RCV001779368 | SCV002559132 | likely pathogenic | Febrile seizures, familial, 8 | criteria provided, single submitter | clinical testing | ||
| Labcorp Genetics |
RCV002541096 | SCV003301187 | pathogenic | Epilepsy, childhood absence 2; Febrile seizures, familial, 8 | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 125 of the GABRG2 protein (p.Arg125Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of developmental and epileptic encephalopathy (PMID: 35359574; Invitae). ClinVar contains an entry for this variant (Variation ID: 1321267). 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 GABRG2 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg125 amino acid residue in GABRG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV001779368 | SCV003921972 | pathogenic | Febrile seizures, familial, 8 | 2023-07-16 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both generalized and familial febrile seizures (MIM#607681), and developmental and epileptic encephalopathy 74 (MIM#618396) (PMID: 27864268). Dominant negative is also a suggested mechanism, however the functional assays are inconclusive (PMID: 27367160). (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 neurotransmitter-gated ion-channel ligand binding domain (DECIPHER). (I) 0704 – Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg125Pro)) has been reported in an individual with febrile seizures (PMID: 35359574). (SP) 0802 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS and as likely pathogenic, and observed in at least three individuals with febrile seizures (ClinVar, PMID: 35359574). (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) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |