ClinVar Genomic variation as it relates to human health
NM_024009.3(GJB3):c.538C>T (p.Arg180Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024009.3(GJB3):c.538C>T (p.Arg180Ter)
Variation ID: 6486 Accession: VCV000006486.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.3 1: 34785300 (GRCh38) [ NCBI UCSC ] 1: 35250901 (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 30, 2015 Feb 14, 2024 Apr 23, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_024009.3:c.538C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_076872.1:p.Arg180Ter nonsense NM_001005752.2:c.538C>T NP_001005752.1:p.Arg180Ter nonsense NC_000001.11:g.34785300C>T NC_000001.10:g.35250901C>T NG_008309.1:g.9112C>T - Protein change
- R180*
- Other names
- -
- Canonical SPDI
- NC_000001.11:34785299:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
---|---|---|---|---|---|---|
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. |
|||
GJB3 | - | - |
GRCh38 GRCh37 |
198 | 210 |
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. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 1998 | RCV000006859.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 15, 2013 | RCV000150742.4 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 23, 2023 | RCV001762035.5 |
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
(Aug 15, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198180.4
First in ClinVar: Jan 30, 2015 Last updated: Jan 30, 2015 |
Comment:
The Arg180X variant in GJB3 has been reported in two individuals with hearing lo ss (Xia 1998, Yao 2013). This variant was shown to segregate … (more)
The Arg180X variant in GJB3 has been reported in two individuals with hearing lo ss (Xia 1998, Yao 2013). This variant was shown to segregate in one individual w ith hearing loss but was also seen in one unaffected family member (Xia 1998). This nonsense variant leads to a premature termination codon at position 180 and the variant has been shown to impact protein function (He 2005). However, evide nce is lacking for a clear association of the GJB3 gene with hearing loss in eit her a recessive or dominant manner. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Dec 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235148.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Apr 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV004291783.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this premature translational stop signal affects GJB3 function (PMID: 16077902, 21204020). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 6486). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 9843210, 29106878, 31564438, 32645618). This variant is present in population databases (rs74315319, gnomAD 0.1%). This sequence change creates a premature translational stop signal (p.Arg180*) in the GJB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the GJB3 protein. (less)
|
|
Uncertain significance
(Apr 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002000750.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in the heterozygous state in patients with hearing loss (Xia et al., 1998; Chen et al., 2011; Yao et al., 2013; Li et al., … (more)
Observed in the heterozygous state in patients with hearing loss (Xia et al., 1998; Chen et al., 2011; Yao et al., 2013; Li et al., 2015; Liu et al., 2016); Reported in multiple individuals without hearing loss or to not differ in frequency between patients with hearing loss and control populations (Yin et al., 2013; Huang et al., 2017; Dai et al., 2019); Nonsense variant predicted to result in protein truncation as the last 91 amino acids are lost, although pathogenic loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 28604950, 19197336, 30245029, 30896630, 21204020, 9843210, 31564438, 16077902, 30589569, 27176802, 23638949, 25262649, 29106878, 31541171, 30235673, 26330914, 23718755, 21917135, 27727359, 28505178) (less)
|
|
Pathogenic
(Dec 01, 1998)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL DOMINANT 2B
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027055.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 16, 2017 |
Comment on evidence:
In a family (NDF005) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; 612644) from the Hunan province of China, Xia et al. (1998) found that 4 … (more)
In a family (NDF005) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; 612644) from the Hunan province of China, Xia et al. (1998) found that 4 individuals carried a heterozygous C-to-T mutation at nucleotide 538 of GJB3, resulting in a stop codon at amino acid 180. Two male carriers, aged 51 and 23, had hearing difficulties with clinical symptoms and audiograms showing high frequency hearing loss beginning after 30 and 20 years of age, respectively. One female carrier, aged 46, had an audiogram similar to that of the 27-year-old carrier in family NDF0006 (see 603324.0004). The other female carrier, aged 43, had normal hearing. (less)
|
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 |
---|---|---|---|---|
The mutation frequencies of GJB2, GJB3, SLC26A4 and MT-RNR1 of patients with severe to profound sensorineural hearing loss in northwest China. | Liu XW | International journal of pediatric otorhinolaryngology | 2020 | PMID: 32645618 |
Concurrent Hearing and Genetic Screening of 180,469 Neonates with Follow-up in Beijing, China. | Dai P | American journal of human genetics | 2019 | PMID: 31564438 |
The relationship between the GJB3 c.538C>T variant and hearing phenotype in the Chinese population. | Huang S | International journal of pediatric otorhinolaryngology | 2017 | PMID: 29106878 |
Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. | Yao G | Acta oto-laryngologica | 2013 | PMID: 23638949 |
Trafficking abnormality and ER stress underlie functional deficiency of hearing impairment-associated connexin-31 mutants. | Xia K | Protein & cell | 2010 | PMID: 21204020 |
Intracellular distribution, assembly and effect of disease-associated connexin 31 mutants in HeLa cells. | He LQ | Acta biochimica et biophysica Sinica | 2005 | PMID: 16077902 |
Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. | Xia JH | Nature genetics | 1998 | PMID: 9843210 |
Text-mined citations for rs74315319 ...
HelpRecord last updated Mar 17, 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.