NM_198904.4(GABRG2):c.373C>T (p.Arg125Cys) AND Febrile seizures, familial, 8

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 16, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001779368.6

Allele description [Variation Report for NM_198904.4(GABRG2):c.373C>T (p.Arg125Cys)]

NM_198904.4(GABRG2):c.373C>T (p.Arg125Cys)

Gene:

GABRG2:gamma-aminobutyric acid type A receptor subunit gamma2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q34

Genomic location:

Preferred name:

NM_198904.4(GABRG2):c.373C>T (p.Arg125Cys)

HGVS:

NC_000005.10:g.162097683C>T
NG_009290.1:g.35042C>T
NM_000816.3:c.373C>T
NM_001375339.1:c.364C>T
NM_001375340.1:c.373C>T
NM_001375341.1:c.373C>T
NM_001375342.1:c.373C>T
NM_001375343.1:c.373C>T
NM_001375344.1:c.373C>T
NM_001375345.1:c.307C>T
NM_001375346.1:c.307C>T
NM_001375347.1:c.286C>T
NM_001375348.1:c.-31-17C>T
NM_001375349.1:c.88C>T
NM_001375350.1:c.-31-17C>T
NM_198903.2:c.373C>T
NM_198904.4:c.373C>TMANE SELECT
NP_000807.2:p.Arg125Cys
NP_001362268.1:p.Arg122Cys
NP_001362269.1:p.Arg125Cys
NP_001362270.1:p.Arg125Cys
NP_001362271.1:p.Arg125Cys
NP_001362272.1:p.Arg125Cys
NP_001362273.1:p.Arg125Cys
NP_001362274.1:p.Arg103Cys
NP_001362275.1:p.Arg103Cys
NP_001362276.1:p.Arg96Cys
NP_001362278.1:p.Arg30Cys
NP_944493.2:p.Arg125Cys
NP_944494.1:p.Arg125Cys
NC_000005.9:g.161524689C>T
NM_198904.2:c.373C>T

Protein change:

R103C

Links:

dbSNP: rs2113325423

NCBI 1000 Genomes Browser:

rs2113325423

Molecular consequence:

NM_001375348.1:c.-31-17C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001375350.1:c.-31-17C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000816.3:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375339.1:c.364C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375340.1:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375341.1:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375342.1:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375343.1:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375344.1:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375345.1:c.307C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375346.1:c.307C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375347.1:c.286C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375349.1:c.88C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198903.2:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198904.4:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Febrile seizures, familial, 8 (FEB8)
Synonyms:: CONVULSIONS, FAMILIAL FEBRILE, 8
Identifiers:: MONDO: MONDO:0011891; MedGen: C1969810; Orphanet: 36387; OMIM: 607681

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002014705	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 25, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002559132	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003921972	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27367160, 27864268, 35359574, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002014705

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 25, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002559132

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

inherited

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003921972

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 16, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome.

Kang JQ, Macdonald RL.

JAMA Neurol. 2016 Aug 1;73(8):1009-16. doi: 10.1001/jamaneurol.2016.0449. Review.

PubMed [citation]

PMID:: 27367160
PMCID:: PMC5426359

De novo GABRG2 mutations associated with epileptic encephalopathies.

Shen D, Hernandez CC, Shen W, Hu N, Poduri A, Shiedley B, Rotenberg A, Datta AN, Leiz S, Patzer S, Boor R, Ramsey K, Goldberg E, Helbig I, Ortiz-Gonzalez XR, Lemke JR, Marsh ED, Macdonald RL.

Brain. 2017 Jan;140(1):49-67. doi: 10.1093/brain/aww272. Epub 2016 Nov 17.

PubMed [citation]

PMID:: 27864268
PMCID:: PMC5226060

See all PubMed Citations (4)

Details of each submission

From 3billion, SCV002014705.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.839, 3Cnet: 0.982, PP3). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV002559132.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921972.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both generalized and familial febrile seizures (MIM#607681), and developmental and epileptic encephalopathy 74 (MIM#618396) (PMID: 27864268). Dominant negative is also a suggested mechanism, however the functional assays are inconclusive (PMID: 27367160). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated neurotransmitter-gated ion-channel ligand binding domain (DECIPHER). (I) 0704 – Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg125Pro)) has been reported in an individual with febrile seizures (PMID: 35359574). (SP) 0802 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS and as likely pathogenic, and observed in at least three individuals with febrile seizures (ClinVar, PMID: 35359574). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 22, 2024

ClinVar

Relating variation to medicine