ClinVar Miner

Submissions for variant NM_198903.2(GABRG2):c.316G>A (p.Ala106Thr) (rs796052505)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000547790 SCV000992706 likely pathogenic Epilepsy, childhood absence 2; Familial febrile seizures 8 2018-10-12 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000547790 SCV000898724 pathogenic Epilepsy, childhood absence 2; Familial febrile seizures 8 2018-08-27 criteria provided, single submitter clinical testing GABRG2 NM_000816.3 exon 3 p.Ala106Thr (c.316G>A): This variant has been reported in the literature in 6 individuals presenting with epilepsy and other features, 5 of whom were identified as de novo (Shen 2017 PMID:27864268; Zou 2017 PMID:28460589). This variant is absent from large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 205541). Evolutionary conservation and computational predictive tools for this variant are unclear. Additionally, in vitro functional studies support that this variant will impact the protein, disrupting channel function (Shen 2017 PMID:27864268). In summary, this variant is classified as pathogenic based on the data above.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000187522 SCV000297409 likely pathogenic not provided 2015-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000187522 SCV000241116 pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing The A106T variant in the GABRG2 gene has been reported previously as a heterozygous, de novo variant in multiple unrelated individuals with variable early-onset seizures, global developmental delays, intellectual disability, hypotonia, movement disorder, inability to walk, dysmorphic features, and vision/ocular issues (Zou et al., 2017; Shen et al., 2017). The A106T variant is not observed in large population cohorts (Lek et al., 2016). The A106T 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 across species. Functional studies of A106T transfected HEK293T cells demonstrated decreased GABA-evoked whole-cell currents and altered kinetic properties of GABA-A receptor currents (Shen et al., 2017). We interpret A106T as a pathogenic variant.
Invitae RCV000547790 SCV000645966 pathogenic Epilepsy, childhood absence 2; Familial febrile seizures 8 2017-04-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 106 of the GABRG2 protein (p.Ala106Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in in several individuals affected with epileptic encephalopathy (PMID:27864268, 27730413). ClinVar contains an entry for this variant (Variation ID: 205541). Experimental evidence suggests this variant results in decreased whole cell currents in transfected cells (PMID: 27864268). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000767869 SCV000898481 pathogenic EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 74 2019-04-19 no assertion criteria provided literature only
Undiagnosed Diseases Network,NIH RCV000767869 SCV000622176 pathogenic EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 74 2016-10-25 criteria provided, single submitter clinical testing Rare de novo variant also identified in 4 other patients with very similar phenotype. Pathogenic given rare de novo variant also identified in four other patients with near identical phenotype, as reported in PMID 28460589. Phenotype includes early-onset seizures, global developmental delay, intellectual disability, hypotonia, movement disorder and vision issues.

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