Submissions for variant NM_198904.4(GABRG2):c.316G>A (p.Ala106Thr)

dbSNP: rs796052505

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187522	SCV000241116	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	Published 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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29346770, 31171384, 31216405, 31087664, 30190672, 27864268, 28460589, 32901917, 32005694)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000187522	SCV000297409	likely pathogenic	not provided	2015-08-19	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000767869	SCV000622176	pathogenic	Developmental and epileptic encephalopathy, 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.
Invitae	RCV000547790	SCV000645966	pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 8	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 106 of the GABRG2 protein (p.Ala106Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27730413, 27864268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205541). 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 not expected to disrupt GABRG2 protein function with a negative 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000547790	SCV000898724	pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 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.
Baylor Genetics	RCV000547790	SCV000992706	likely pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 8	2018-10-12	criteria provided, single submitter	clinical testing
3billion	RCV000767869	SCV002012280	pathogenic	Developmental and epileptic encephalopathy, 74	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000205541.11, PMID: 28460589, 27864268, 27730413, and 31216405, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000767869	SCV002556376	pathogenic	Developmental and epileptic encephalopathy, 74	2021-02-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321755	SCV002610041	pathogenic	Inborn genetic diseases	2018-09-26	criteria provided, single submitter	clinical testing	The p.A106T pathogenic mutation (also known as c.316G>A), located in coding exon 3 of the GABRG2 gene, results from a G to A substitution at nucleotide position 316. The alanine at codon 106 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in multiple individuals with early-onset seizures, development delay, and hypotonia (Shen D et al. Brain, 2017 01;140:49-67; Zou F et al. J. Neurogenet. May;31:30-36). Functional studies of this mutation in HEK293T cells demonstrated a reduced surface level and altered kinetic properties (Shen D et al. Brain, 2017 01;140:49-67). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000187522	SCV003825705	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224207	SCV003919999	pathogenic	Febrile seizures, familial, 8; Developmental and epileptic encephalopathy, 74	2021-11-11	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.
OMIM	RCV000767869	SCV000898481	pathogenic	Developmental and epileptic encephalopathy, 74	2020-11-25	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000187522	SCV001808747	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000187522	SCV001928131	pathogenic	not provided		no assertion criteria provided	clinical testing