ClinVar Genomic variation as it relates to human health
NM_021912.5(GABRB3):c.31C>T (p.Pro11Ser)
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.
Uncertain significance(1); Benign(8); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021912.5(GABRB3):c.31C>T (p.Pro11Ser)
Variation ID: 16191 Accession: VCV000016191.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q12 15: 27018841 (GRCh37) [ NCBI UCSC ] 15: 26773694 (GRCh38) [ 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 Dec 27, 2015 May 1, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021912.5:c.31C>T NP_068712.1:p.Pro11Ser missense NC_000015.10:g.26773694G>A NC_000015.9:g.27018841G>A NG_012836.1:g.5087C>T - Protein change
- P11S
- Other names
- -
- Canonical SPDI
- NC_000015.10:26773693: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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0.00200 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00200
1000 Genomes Project 30x 0.00203
The Genome Aggregation Database (gnomAD), exomes 0.00291
The Genome Aggregation Database (gnomAD) 0.00354
Trans-Omics for Precision Medicine (TOPMed) 0.00376
Exome Aggregation Consortium (ExAC) 0.00582
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 | ||
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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
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. |
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GABRB3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
624 | 937 |
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. |
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Uncertain significance (2) |
criteria provided, single submitter
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May 2, 2016 | RCV000017575.15 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2016 | RCV000203153.13 | |
Benign (5) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV001701568.21 | |
Benign (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000989276.9 | |
Benign (1) |
criteria provided, single submitter
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Sep 16, 2016 | RCV002313713.9 | |
Benign (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV001511952.13 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 24, 2022 | RCV003224101.8 | |
Benign (1) |
criteria provided, single submitter
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Jun 5, 2020 | RCV003934836.1 |
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. |
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Likely benign
(May 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000258180.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
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Benign
(Dec 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000613366.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Uncertain significance
(May 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, childhood absence, susceptibility to, 5
Affected status: unknown
Allele origin:
paternal
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782445.1
First in ClinVar: Sep 23, 2016 Last updated: Sep 23, 2016 |
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, childhood absence, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139532.1
First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020 |
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Benign
(Apr 08, 2019)
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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: SCV000513096.4
First in ClinVar: Mar 08, 2017 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 26645412, 22206818, 20550555, 19935738, 18514161, 20308251, 27884173, 31435640)
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Likely benign
(Oct 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, childhood absence, susceptibility to, 5
Developmental and epileptic encephalopathy, 43
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003919997.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
GABRB3 NM_021912.5 exon 1 p.Pro11Ser (c.31C>T): This variant has been reported in the literature in at least 2 individuals with absence epilepsy and numerous individuals … (more)
GABRB3 NM_021912.5 exon 1 p.Pro11Ser (c.31C>T): This variant has been reported in the literature in at least 2 individuals with absence epilepsy and numerous individuals with autism (Tanaka 2008 PMID:185141461, Delahanty 2011 PMID:19935738). However, this variant is present in 0.5% (370/67998) of European alleles including 2 homozygotes, as well as 1 homozygote in the South Asian population in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-26773694-G-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:16191). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies suggests that this variant may impact the protein, however, this data may not represent in vivo biological function (Tanaka 2008 PMID:185141461, Shi 2019 PMID:31435640). In summary, data on this variant, particularly the minor allele frequency and presence of homozygotes in ostensibly unaffected individuals suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as Likely Benign. (less)
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Benign
(Oct 13, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564680.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
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Benign
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, childhood absence, susceptibility to, 5
Epilepsy, childhood absence, susceptibility to, 1
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: SCV001719277.3
First in ClinVar: Jun 15, 2021 Last updated: Feb 28, 2024 |
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Benign
(Jun 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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GABRB3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004752053.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Benign
(Jan 01, 2024)
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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: SCV002497748.12
First in ClinVar: Apr 12, 2022 Last updated: Apr 15, 2024 |
Comment:
GABRB3: PP2, BP4, BS1, BS2
Number of individuals with the variant: 15
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Benign
(Sep 16, 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: SCV000849397.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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risk factor
(Jun 01, 2008)
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no assertion criteria provided
Method: literature only
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EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037847.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 23, 2016 |
Comment on evidence:
In affected members of 2 unrelated Mexican families with childhood absence epilepsy-5 (ECA5; 612269), Tanaka et al. (2008) identified a heterozygous 31C-T transition in exon … (more)
In affected members of 2 unrelated Mexican families with childhood absence epilepsy-5 (ECA5; 612269), Tanaka et al. (2008) identified a heterozygous 31C-T transition in exon 1a of the GABRB3 gene, resulting in a pro11-to-ser (P11S) substitution in the alternative signal peptide. A total of 3 unaffected family members from both families carried the mutation, indicating incomplete penetrance. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. Tanaka et al. (2008) did not identify the P11S mutation in 630 controls, but noted that it is listed as rs25409 in the SNP database. (less)
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Likely benign
(-)
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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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932694.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely benign
(-)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966306.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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Epileptic encephalopathy de novo GABRB mutations impair γ-aminobutyric acid type A receptor function. | Janve VS | Annals of neurology | 2016 | PMID: 26950270 |
Comprehensive molecular testing in patients with high functioning autism spectrum disorder. | Alvarez-Mora MI | Mutation research | 2016 | PMID: 26845707 |
Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. | Reinthaler EM | Annals of neurology | 2015 | PMID: 25726841 |
Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. | Delahanty RJ | Molecular psychiatry | 2011 | PMID: 19935738 |
Screening of GABRB3 in French-Canadian families with idiopathic generalized epilepsy. | Lachance-Touchette P | Epilepsia | 2010 | PMID: 20550555 |
Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. | Tanaka M | American journal of human genetics | 2008 | PMID: 18514161 |
Text-mined citations for rs25409 ...
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.