Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV004771805 | SCV000241124 | pathogenic | not provided | 2022-06-03 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect; specifically, expression of R323W in HEK293 cells led to significantly reduced GABA-evoked currents, increased zinc sensitivity and reduced surface expression, and altered receptor kinetics by accelerating channel deactivation (Shen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28684954, 27864268, 30190672, 31087664, 29933521, 35359574) |
Labcorp Genetics |
RCV000196679 | SCV000254658 | pathogenic | Epilepsy, childhood absence 2; Febrile seizures, familial, 8 | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 323 of the GABRG2 protein (p.Arg323Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epilepsy (PMID: 27864268; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 205549). 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%. Experimental studies have shown that this missense change affects GABRG2 function (PMID: 27864268). This variant disrupts the p.Arg323 amino acid residue in GABRG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187). 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. |
Diagnostic Laboratory, |
RCV001260612 | SCV001437704 | likely pathogenic | Intellectual disability | 2020-09-10 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV003448280 | SCV004175963 | pathogenic | Febrile seizures, familial, 8 | 2023-11-10 | criteria provided, single submitter | clinical testing | Criteria applied: PS2_VSTR,PS4_MOD,PM1,PM5,PS3_SUP,PM2,PP3 |
Institute of Human Genetics, |
RCV003491934 | SCV004239238 | pathogenic | Febrile seizures, familial, 8; Developmental and epileptic encephalopathy, 74 | 2023-12-06 | criteria provided, single submitter | clinical testing |