ClinVar Miner

Submissions for variant NM_000814.6(GABRB3):c.329A>G (p.Asn110Ser)

gnomAD frequency: 0.00001  dbSNP: rs751329477
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001562969 SCV001785826 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001865984 SCV002251079 uncertain significance Epilepsy, childhood absence, susceptibility to, 1; Epilepsy, childhood absence, susceptibility to, 5 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the GABRB3 protein (p.Asn110Ser). This variant is present in population databases (rs751329477, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of GABRB3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 1198718). 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) has been performed at Invitae 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 GABRB3 protein function. This variant disrupts the p.Asn110 amino acid residue in GABRB3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23934111, 26950270). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002458528 SCV002611988 uncertain significance Inborn genetic diseases 2017-11-20 criteria provided, single submitter clinical testing The p.N110S variant (also known as c.329A>G), located in coding exon 4 of the GABRB3 gene, results from an A to G substitution at nucleotide position 329. The asparagine at codon 110 is replaced by serine, an amino acid with highly similar properties. An alternate substitution at this position, p.N110D, was detected in an individual diagnosed with epileptic encephalopathy and has been reported to impair GABAA receptor current kinetic properties (Allen et al. Nature, 2013 Sep;501:217-21; Janve VS et al. Ann. Neurol., 2016 Mar [Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of the p.N110S alteration remains unclear.

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