ClinVar Genomic variation as it relates to human health
NM_001127644.2(GABRA1):c.335G>A (p.Arg112Gln)
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.
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(5); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001127644.2(GABRA1):c.335G>A (p.Arg112Gln)
Variation ID: 127074 Accession: VCV000127074.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q34 5: 161873196 (GRCh38) [ NCBI UCSC ] 5: 161300202 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 24, 2014 May 1, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127644.2:c.335G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121116.1:p.Arg112Gln missense NM_000806.5:c.335G>A NP_000797.2:p.Arg112Gln missense NM_001127643.2:c.335G>A NP_001121115.1:p.Arg112Gln missense NM_001127645.2:c.335G>A NP_001121117.1:p.Arg112Gln missense NM_001127648.2:c.335G>A NP_001121120.1:p.Arg112Gln missense NC_000005.10:g.161873196G>A NC_000005.9:g.161300202G>A NG_011548.1:g.31006G>A P14867:p.Arg112Gln - Protein change
- R112Q
- Other names
- p.R112Q:CGG>CAG
- Canonical SPDI
- NC_000005.10:161873195:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GABRA1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
651 | 684 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
no assertion criteria provided
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Apr 8, 2014 | RCV000114937.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2016 | RCV000623344.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV000705072.17 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Dec 1, 2022 | RCV000153292.38 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2017 | RCV000760281.9 |
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
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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
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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
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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. |
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Pathogenic
(Sep 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000241089.14
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Previously reported as a likely pathogenic variant in a patient with epilepsy; however, no further clinical or segregation information was provided (Butler et al., 2017); … (more)
Previously reported as a likely pathogenic variant in a patient with epilepsy; however, no further clinical or segregation information was provided (Butler 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: 24623842, 26918889, 26073591, 29056246, 31056671, 27521439) (less)
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Pathogenic
(Oct 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000847991.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R112Q pathogenic mutation (also known as c.335G>A), located in coding exon 4 of the GABRA1 gene, results from a G to A substitution at … (more)
The p.R112Q pathogenic mutation (also known as c.335G>A), located in coding exon 4 of the GABRA1 gene, results from a G to A substitution at nucleotide position 335. The arginine at codon 112 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 one individual with epileptic encephalopathy in our laboratory. In addition, this variant has been reported in two individuals in the literature with epileptic encephalopathy, one of which was reportedly de novo (Carvill GL et al. Neurology, 2014 Apr;82:1245-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Uncertain significance
(Apr 16, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000202769.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 19
Epilepsy, idiopathic generalized, susceptibility to, 13 Epilepsy, idiopathic generalized, susceptibility to, 13 (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890121.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
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Pathogenic
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, childhood absence 4
Epilepsy, idiopathic generalized, susceptibility to, 13 Idiopathic generalized epilepsy
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
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Invitae
Accession: SCV000834052.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 112 of the GABRA1 protein (p.Arg112Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 112 of the GABRA1 protein (p.Arg112Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a variety of seizure phenotypes including early infantile epilepsy and Dravet syndrome (PMID: 24623842, 26918889, 27521439). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127074). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GABRA1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247874.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
GABRA1: PM6:Strong, PM1, PM2, PS4:Moderate, PP2
Number of individuals with the variant: 2
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Pathogenic
(Apr 08, 2014)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 19
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000148835.2
First in ClinVar: Apr 24, 2014 Last updated: Oct 25, 2020 |
Comment on evidence:
In 2 unrelated patients (T16706 and T23532) with developmental and epileptic encephalopathy-19 (DEE19; 615744), Carvill et al. (2014) identified a heterozygous c.335G-A transition in the … (more)
In 2 unrelated patients (T16706 and T23532) with developmental and epileptic encephalopathy-19 (DEE19; 615744), Carvill et al. (2014) identified a heterozygous c.335G-A transition in the GABRA1 gene, resulting in an arg112-to-gln (R112Q) substitution at a highly conserved residue. The mutation was confirmed to occur de novo in 1 patient; parental DNA was not available from the second patient. Functional studies of the variant were not performed. The patients had onset of febrile seizures at 11 months of age. The phenotype was consistent with a clinical diagnosis of Dravet syndrome. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809444.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951088.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 19
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001984753.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. | Johannesen K | Neurology | 2016 | PMID: 27521439 |
De novo GABRA1 mutations in Ohtahara and West syndromes. | Kodera H | Epilepsia | 2016 | PMID: 26918889 |
GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. | Carvill GL | Neurology | 2014 | PMID: 24623842 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GABRA1 | - | - | - | - |
Text-mined citations for rs587777308 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.