Submissions for variant NM_198904.4(GABRG2):c.968G>A (p.Arg323Gln)

dbSNP: rs397514737

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187531	SCV000241125	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015; Absalom et al., 2019); This variant is associated with the following publications: (PMID: 27864268, 27334371, 29720203, 29358611, 29100083, 31139143, 25726841, 23708187, 28191890, 31087664, 30728247, 28351718, 25730860, 28714951)
Ambry Genetics	RCV002316207	SCV000851296	pathogenic	Inborn genetic diseases	2016-10-12	criteria provided, single submitter	clinical testing	The p.R323Q pathogenic mutation (also known as c.968G>A), located in coding exon 8 of the GABRG2 gene, results from a G to A substitution at nucleotide position 968. The arginine at codon 323 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been determined to be the result of a de novo mutation in two patients with epileptic encephalopathies (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30; Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Electrophysiology functional studies indicate this variant results in altered GABAA-R chloride channel kinetics (Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057395	SCV001221884	pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 8	2024-01-27	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 323 of the GABRG2 protein (p.Arg323Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABRG2-related conditions (PMID: 23708187, 27864268, 29100083, 29358611). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60708). 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). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000187531	SCV001247879	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001268930	SCV005417149	pathogenic	Developmental and epileptic encephalopathy, 74		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PM6_VeryStrong+PS3_Moderate+PP2
OMIM	RCV000054505	SCV000082983	pathogenic	Generalized epilepsy with febrile seizures plus 3	2013-07-01	no assertion criteria provided	literature only
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000655995	SCV000588271	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
OMIM	RCV001268930	SCV001448180	pathogenic	Developmental and epileptic encephalopathy, 74	2013-07-01	no assertion criteria provided	literature only