VCV000060708.44 - ClinVar

NM_198904.4(GABRG2):c.968G>A (p.Arg323Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_198904.4(GABRG2):c.968G>A (p.Arg323Gln)

Variation ID: 60708 Accession: VCV000060708.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q34 5: 162149153 (GRCh38) [ NCBI UCSC ] 5: 161576159 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 7, 2017	Nov 30, 2024	Jan 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_198904.4:c.968G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_944494.1:p.Arg323Gln	missense
NM_000816.3:c.968G>A	NP_000807.2:p.Arg323Gln	missense
NM_001375339.1:c.959G>A	NP_001362268.1:p.Arg320Gln	missense
NM_001375340.1:c.923-2577G>A		intron variant
NM_001375341.1:c.965G>A	NP_001362270.1:p.Arg322Gln	missense
NM_001375342.1:c.965G>A	NP_001362271.1:p.Arg322Gln	missense
NM_001375343.1:c.1088G>A	NP_001362272.1:p.Arg363Gln	missense
NM_001375344.1:c.1007G>A	NP_001362273.1:p.Arg336Gln	missense
NM_001375345.1:c.902G>A	NP_001362274.1:p.Arg301Gln	missense
NM_001375346.1:c.902G>A	NP_001362275.1:p.Arg301Gln	missense
NM_001375347.1:c.881G>A	NP_001362276.1:p.Arg294Gln	missense
NM_001375348.1:c.548G>A	NP_001362277.1:p.Arg183Gln	missense
NM_001375349.1:c.683G>A	NP_001362278.1:p.Arg228Gln	missense
NM_001375350.1:c.548G>A	NP_001362279.1:p.Arg183Gln	missense
NM_198903.2:c.1088G>A	NP_944493.2:p.Arg363Gln	missense
NC_000005.10:g.162149153G>A
NC_000005.9:g.161576159G>A
NG_009290.1:g.86512G>A

... more HGVS ... less HGVS

Protein change

R323Q, R363Q, R183Q, R228Q, R294Q, R301Q, R320Q, R322Q, R336Q

Other names

p.R323Q:CGG>CAG

Canonical SPDI

NC_000005.10:162149152:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA144631 OMIM: 137164.0006 dbSNP: rs397514737 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GABRG2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	677	713

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Generalized epilepsy with febrile seizures plus 3	Pathogenic (1)	no assertion criteria provided	Jul 1, 2013	RCV000054505.38
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 1, 2021	RCV000187531.33
Childhood epilepsy with centrotemporal spikes	Pathogenic (1)	no assertion criteria provided	Jan 1, 2017	RCV000655995.8
Epilepsy, childhood absence 2 Febrile seizures, familial, 8	Pathogenic (1)	criteria provided, single submitter	Jan 27, 2024	RCV001057395.13
Developmental and epileptic encephalopathy, 74	Pathogenic (2)	criteria provided, single submitter	-	RCV001268930.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2016	RCV002316207.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000241125.14 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015; Absalom et al., 2019); This variant is associated with the following publications: (PMID: 27864268, … (more) Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015; Absalom et al., 2019); This variant is associated with the following publications: (PMID: 27864268, 27334371, 29720203, 29358611, 29100083, 31139143, 25726841, 23708187, 28191890, 31087664, 30728247, 28351718, 25730860, 28714951) (less)
Pathogenic (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Febrile seizures, familial, 8 Epilepsy, childhood absence 2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001221884.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 23708187‚ 27864268‚ 29100083‚ 29358611 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 323 of the GABRG2 protein (p.Arg323Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 323 of the GABRG2 protein (p.Arg323Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABRG2-related conditions (PMID: 23708187, 27864268, 29100083, 29358611). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60708). 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). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 12, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000851296.4 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 23708187‚ 25726841‚ 25730860 Comment: The p.R323Q pathogenic mutation (also known as c.968G>A), located in coding exon 8 of the GABRG2 gene, results from a G to A substitution at … (more) The p.R323Q pathogenic mutation (also known as c.968G>A), located in coding exon 8 of the GABRG2 gene, results from a G to A substitution at nucleotide position 968. The arginine at codon 323 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been determined to be the result of a de novo mutation in two patients with epileptic encephalopathies (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30; Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Electrophysiology functional studies indicate this variant results in altered GABAA-R chloride channel kinetics (Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247879.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 74 Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005417149.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PS4+PM6_VeryStrong+PS3_Moderate+PP2
Pathogenic (Jul 01, 2013)	no assertion criteria provided Method: literature only	GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000082983.5 First in ClinVar: Aug 21, 2013 Last updated: Nov 28, 2020	Publications: PubMed (2) PubMed: 23708187‚ 27864268 Comment on evidence: Generalized Epilepsy with Febrile Seizures Plus, Type 3 In a 2.5-year-old boy with generalized epilepsy with febrile seizures plus (see 607681), Carvill et al. (2013) … (more) Generalized Epilepsy with Febrile Seizures Plus, Type 3 In a 2.5-year-old boy with generalized epilepsy with febrile seizures plus (see 607681), Carvill et al. (2013) identified a de novo heterozygous mutation in the GABRG2 gene, resulting in an arg323-to-gln (R323Q) substitution. The patient had onset of febrile seizures at age 8 months, followed by absence seizures, atonic seizures, myoclonic jerks, and tonic-clonic seizures. EEG was normal and he had normal development. The patient was ascertained from a large cohort of 500 patients with epileptic encephalopathy who underwent candidate gene sequencing; this was the only patient found to carry a GABRG2 mutation. Developmental and Epileptic Encephalopathy 74 In 2 unrelated girls (patients 5 and 6) with developmental and epileptic encephalopathy-74 (DEE74; 618396), Shen et al. (2017) identified a de novo heterozygous c.968G-A transition in the GABRG2 gene, resulting in an R323Q substitution at a highly conserved residue in the pore-forming M2 domain. In vitro functional expression studies in transfected HEK293 cells showed that the R323Q mutation decreased channel current by about 50%, increased zinc inhibition by about 25%, had reduced surface expression (about 50%), and had decreased response to GABA compared to wildtype. The patients had onset of intractable focal and myoclonic seizures between 10 and 12 months of age. (less)
Pathogenic (Jul 01, 2013)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 74 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001448180.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Publications: PubMed (2) PubMed: 23708187‚ 27864268 Comment on evidence: Generalized Epilepsy with Febrile Seizures Plus, Type 3 In a 2.5-year-old boy with generalized epilepsy with febrile seizures plus (see 607681), Carvill et al. (2013) … (more) Generalized Epilepsy with Febrile Seizures Plus, Type 3 In a 2.5-year-old boy with generalized epilepsy with febrile seizures plus (see 607681), Carvill et al. (2013) identified a de novo heterozygous mutation in the GABRG2 gene, resulting in an arg323-to-gln (R323Q) substitution. The patient had onset of febrile seizures at age 8 months, followed by absence seizures, atonic seizures, myoclonic jerks, and tonic-clonic seizures. EEG was normal and he had normal development. The patient was ascertained from a large cohort of 500 patients with epileptic encephalopathy who underwent candidate gene sequencing; this was the only patient found to carry a GABRG2 mutation. Developmental and Epileptic Encephalopathy 74 In 2 unrelated girls (patients 5 and 6) with developmental and epileptic encephalopathy-74 (DEE74; 618396), Shen et al. (2017) identified a de novo heterozygous c.968G-A transition in the GABRG2 gene, resulting in an R323Q substitution at a highly conserved residue in the pore-forming M2 domain. In vitro functional expression studies in transfected HEK293 cells showed that the R323Q mutation decreased channel current by about 50%, increased zinc inhibition by about 25%, had reduced surface expression (about 50%), and had decreased response to GABA compared to wildtype. The patients had onset of intractable focal and myoclonic seizures between 10 and 12 months of age. (less)
Pathogenic (Jan 01, 2017)	no assertion criteria provided Method: case-control	Childhood epilepsy with centrotemporal spikes Affected status: yes Allele origin: germline	Bioinformatics Core, Luxembourg Center for Systems Biomedicine Study: EUROEPINOMICS COGIE Accession: SCV000588271.1 First in ClinVar: Jun 01, 2018 Last updated: Jun 01, 2018	Publications: PubMed (1) PubMed: 29358611 Comment: CAADphred>15

Comment:

Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015; Absalom et al., 2019); This variant is associated with the following publications: (PMID: 27864268, 27334371, 29720203, 29358611, 29100083, 31139143, 25726841, 23708187, 28191890, 31087664, 30728247, 28351718, 25730860, 28714951)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 323 of the GABRG2 protein (p.Arg323Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABRG2-related conditions (PMID: 23708187, 27864268, 29100083, 29358611). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60708). 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). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R323Q pathogenic mutation (also known as c.968G>A), located in coding exon 8 of the GABRG2 gene, results from a G to A substitution at nucleotide position 968. The arginine at codon 323 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been determined to be the result of a de novo mutation in two patients with epileptic encephalopathies (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30; Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Electrophysiology functional studies indicate this variant results in altered GABAA-R chloride channel kinetics (Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.	Bobbili DR	European journal of human genetics : EJHG	2018	PMID: 29358611
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.	Hamdan FF	American journal of human genetics	2017	PMID: 29100083
De novo GABRG2 mutations associated with epileptic encephalopathies.	Shen D	Brain : a journal of neurology	2017	PMID: 27864268
Allosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure.	Moraga-Cid G	Proceedings of the National Academy of Sciences of the United States of America	2015	PMID: 25730860
Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes.	Reinthaler EM	Annals of neurology	2015	PMID: 25726841
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.	Carvill GL	Nature genetics	2013	PMID: 23708187

Text-mined citations for rs397514737 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_198904.4(GABRG2):c.968G>A (p.Arg323Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397514737 ...