VCV000093433.25 - ClinVar

NM_198904.4(GABRG2):c.1000G>A (p.Ala334Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(2)

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_198904.4(GABRG2):c.1000G>A (p.Ala334Thr)

Variation ID: 93433 Accession: VCV000093433.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q34 5: 162149185 (GRCh38) [ NCBI UCSC ] 5: 161576191 (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	Dec 19, 2017	Apr 13, 2025	Jul 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_198904.4:c.1000G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_944494.1:p.Ala334Thr	missense
NM_000816.3:c.1000G>A	NP_000807.2:p.Ala334Thr	missense
NM_001375339.1:c.991G>A	NP_001362268.1:p.Ala331Thr	missense
NM_001375340.1:c.923-2545G>A		intron variant
NM_001375341.1:c.997G>A	NP_001362270.1:p.Ala333Thr	missense
NM_001375342.1:c.997G>A	NP_001362271.1:p.Ala333Thr	missense
NM_001375343.1:c.1120G>A	NP_001362272.1:p.Ala374Thr	missense
NM_001375344.1:c.1039G>A	NP_001362273.1:p.Ala347Thr	missense
NM_001375345.1:c.934G>A	NP_001362274.1:p.Ala312Thr	missense
NM_001375346.1:c.934G>A	NP_001362275.1:p.Ala312Thr	missense
NM_001375347.1:c.913G>A	NP_001362276.1:p.Ala305Thr	missense
NM_001375348.1:c.580G>A	NP_001362277.1:p.Ala194Thr	missense
NM_001375349.1:c.715G>A	NP_001362278.1:p.Ala239Thr	missense
NM_001375350.1:c.580G>A	NP_001362279.1:p.Ala194Thr	missense
NM_198903.2:c.1120G>A	NP_944493.2:p.Ala374Thr	missense
NC_000005.10:g.162149185G>A
NC_000005.9:g.161576191G>A
NG_009290.1:g.86544G>A

... more HGVS ... less HGVS

Protein change

A334T, A374T, A194T, A239T, A305T, A312T, A331T, A333T, A347T

Other names

Canonical SPDI

NC_000005.10:162149184: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA221363 dbSNP: rs398123523 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	725	761

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.
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Jul 26, 2024	RCV000518838.24
EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 Febrile seizures, familial, 8	Likely pathogenic (1)	criteria provided, single submitter	May 15, 2024	RCV000797789.18

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.
Uncertain significance (Sep 13, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099128.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PM2
Likely pathogenic (May 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Febrile seizures, familial, 8 EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 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: SCV000937368.7 First in ClinVar: Aug 14, 2019 Last updated: Mar 04, 2025	Publications: PubMed (1) PubMed: 36403551 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the GABRG2 protein (p.Ala334Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the GABRG2 protein (p.Ala334Thr). This variant is present in population databases (rs398123523, gnomAD 0.0009%). This missense change has been observed in individuals with GABRG2-related conditions (PMID: 36403551; Invitae). ClinVar contains an entry for this variant (Variation ID: 93433). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Aug 09, 2013) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111189.9 First in ClinVar: Jan 17, 2014 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GABRG2 Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Jul 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000515993.9 First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30190672, 36403551) (less)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the GABRG2 protein (p.Ala334Thr). This variant is present in population databases (rs398123523, gnomAD 0.0009%). This missense change has been observed in individuals with GABRG2-related conditions (PMID: 36403551; Invitae). ClinVar contains an entry for this variant (Variation ID: 93433). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30190672, 36403551)

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
Genetic Diagnosis Impacts Medical Management for Pediatric Epilepsies.	Haviland I	Pediatric neurology	2023	PMID: 36403551
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GABRG2	-	-	-	-

Text-mined citations for rs398123523 ...

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 Apr 28, 2025

ClinVar Genomic variation as it relates to human health

NM_198904.4(GABRG2):c.1000G>A (p.Ala334Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123523 ...