Submissions for variant NM_198904.4(GABRG2):c.967C>T (p.Arg323Trp)

dbSNP: rs796052510

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187530	SCV000241124	uncertain significance	not specified	2014-12-15	criteria provided, single submitter	clinical testing	p.Arg323Trp (CGG>TGG): c.967 C>T in exon 8 of the GABRG2 gene (NM_000816.3) The R323W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R323W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, Tryptophan is observed at this position in a more distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the R323W variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Invitae	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, Strasbourg University Hospital	RCV001260612	SCV001437704	likely pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	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_SUP,PP3
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV003491934	SCV004239238	pathogenic	Febrile seizures, familial, 8; Developmental and epileptic encephalopathy, 74	2023-12-06	criteria provided, single submitter	clinical testing