Submissions for variant NM_198904.4(GABRG2):c.530G>A (p.Arg177Gln)

gnomAD frequency: 0.00001  dbSNP: rs1445637165

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691540	SCV000819324	likely pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 8	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 177 of the GABRG2 protein (p.Arg177Gln). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of GABRG2-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 570636). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GABRG2 protein function. This variant disrupts the p.Arg177 amino acid residue in GABRG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16924025, 24874541). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Illumina Laboratory Services, Illumina	RCV001156133	SCV001317619	uncertain significance	Epilepsy, childhood absence 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV004760713	SCV005373228	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30190672, 28102150, 16924025)