ClinVar Miner

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

dbSNP: rs796052510
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Total submissions: 5
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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

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