Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002450499 | SCV002732743 | likely pathogenic | Inborn genetic diseases | 2019-04-11 | criteria provided, single submitter | clinical testing | The p.R82W variant (also known as c.244C>T), located in coding exon 2 of the GABRG2 gene, results from a C to T substitution at nucleotide position 244. The arginine at codon 82 is replaced by tryptophan, an amino acid with dissimilar properties. A different alteration at the same position (p.R82Q, reported as p.R43Q) co-segregated with childhood absence epilepsy and febrile seizures in a large family (Wallace RH et al. Nat. Genet., 2001 May;28:49-52). An in vitro study demonstrated that p.R82Q reduces surface expression of GABAA receptors (Huang X et al. Neurobiol. Dis., 2014 Aug;68:167-79), and Gabrg2 knockin mouse harboring this alteration also recapitulated the seizure phenotype observed in patients (Tan HO et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Oct;104:17536-41). Based on internal structural analysis, p.R82W is anticipated to result in a significant decrease in structural stability (Zhu S et al. Nature, 2018 07;559:67-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV003101833 | SCV003447064 | pathogenic | Epilepsy, childhood absence 2; Febrile seizures, familial, 8 | 2024-01-22 | 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 82 of the GABRG2 protein (p.Arg82Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of generalized epilepsy with febrile seizures plus (Invitae). ClinVar contains an entry for this variant (Variation ID: 1791457). 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%. This variant disrupts the p.Arg82 amino acid residue in GABRG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11326275, 12097483, 15470132, 25731747). 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. |