ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.23C>T (p.Thr8Met)
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
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NM_004004.6(GJB2):c.23C>T (p.Thr8Met)
Variation ID: 379889 Accession: VCV000379889.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189559 (GRCh38) [ NCBI UCSC ] 13: 20763698 (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 Dec 19, 2017 Apr 15, 2024 Oct 31, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.23C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Thr8Met missense NC_000013.11:g.20189559G>A NC_000013.10:g.20763698G>A NG_008358.1:g.8417C>T LRG_1350:g.8417C>T LRG_1350t1:c.23C>T LRG_1350p1:p.Thr8Met - Protein change
- T8M
- Other names
- NM_004004.6(GJB2):c.23C>T
- p.Thr8Met
- Canonical SPDI
- NC_000013.11:20189558: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 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 | ||
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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
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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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
556 | 617 |
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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2021 | RCV000429597.21 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 22, 2021 | RCV000988961.8 | |
Uncertain significance (2) |
reviewed by expert panel
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Oct 31, 2022 | RCV001257044.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 5, 2022 | RCV001420843.3 |
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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Uncertain significance
(Oct 31, 2022)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV003800589.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
The c.23C>T variant in GJB2 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 8. The highest population minor … (more)
The c.23C>T variant in GJB2 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 8. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002511 (13/30616 alleles with no homozygotes) in the South Asian population (no population codes met). The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function. Dual whole cell voltage clamp and dye transfer assays in HeLa cells demonstrated that even though potassium permeability remains the same in the variant, there is a reduction in cationic and large molecules dye transfer compared to WT (PMID:18684989) (PS3_Supporting). This variant has been detected in at least two individuals with autosomal recessive NSHL. One was compound heterozygous for the variant and a pathogenic variant, c.109G>A (p.Val37Ile), with phase unknown (0.5 PM3 points, PMID: 22384008). One individual was homozygous for the variant (0.5 PM3 points, PMID: 31162818) (PM3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PS3_Supporting (Hearing Loss VCEP specifications version 2; 10/31/2022). (less)
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138913.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely pathogenic
(Sep 28, 2018)
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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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Athena Diagnostics Inc
Accession: SCV001143662.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Conflicting … (more)
The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Conflicting predictions of the effect on the protein. Damaging to protein function(s) relevant to disease mechanism. (less)
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Uncertain significance
(Aug 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001433595.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.23C>T, p.Thr8Met variant in GJB2 gene is 0,025% … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.23C>T, p.Thr8Met variant in GJB2 gene is 0,025% (13/30616 South Asian alleles with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) which meets the criteria to apply to PM2_Supporting. Functional studies in HeLa cells using dual whole cell voltage clamp and dye transfer assay demonstrated that even though potassium permeability remains the same in CX26 mutant, there is a reduction in cationic and large molecules dye transfer compared to WT (PMID:18684989). Hence PS3 criteria was downgraded to Supporting strength: PS3_Supporting. This variant has been identified several times with the benign variant p.Val153Ile suggesting that both variants are in cis phase (PMID: 24529908, 11556849, 26096904 and 24158611). The c.23C>T variant has been identified once in homozygous state and with p.Val37Ile variant with unknown phase in patients with hearing loss (PMID: 31162818, 22384008; PM3). Computational evidence did not suggest a relevant impact of the mutation to the protein (REVEL: 0,632), neither PP3 nor BP4 rules applied. In summary, the clinical significance of this variant is currently uncertain (PM2_Supporting, PS3_Supporting, PM3). (less)
Number of individuals with the variant: 1
Clinical Features:
Postlingual moderate hearing loss (present)
Family history: no
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Likely pathogenic
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
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Pars Genome Lab
Accession: SCV001652838.1
First in ClinVar: May 28, 2021 Last updated: May 28, 2021 |
Sex: mixed
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Likely pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810446.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Likely pathogenic
(Apr 12, 2021)
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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: SCV000517380.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
Reported previously in the heterozygous state in multiple individuals with hearing loss, most commonly in cis with the V153I variant, which has been suggested to … (more)
Reported previously in the heterozygous state in multiple individuals with hearing loss, most commonly in cis with the V153I variant, which has been suggested to be benign (Kenna et al., 2001; Dalamon et al., 2005; Snoeckx et al., 2005; Primignani et al., 2009; Bonyadi et al., 2014; Amorini et al., 2015; Burke et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27792752, 12172394, 25388846, 15241677, 18684989, 11556849, 15964725, 26778469, 15954104, 26178431, 24529908, 20497192, 19371219, 22384008, 26096904, 29605365, 29542069, 30730013, 26188157, 31162818, 30275481, 33096615) (less)
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Uncertain significance
(Apr 05, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623245.2
First in ClinVar: May 23, 2021 Last updated: May 16, 2022 |
Comment:
Variant summary: GJB2 c.23C>T (p.Thr8Met) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four … (more)
Variant summary: GJB2 c.23C>T (p.Thr8Met) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250080 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (8e-05 vs 0.026), allowing no conclusion about variant significance. c.23C>T has been widely reported in the literature in individuals affected with Non-Syndromic Hearing Loss ranging from severe profound bilateral (example, Dalamon_2005), moderate high frequency (example, Wu_2002) and mixed with moderate (example, Kenna_2001). In a cross sectional review of the associated literature, this variant was predominantly reported along with a benign/likely benign variant, namely p.Val153Ile in hearing loss cohorts (example, Dalamon_2005, Wu_2002, Kenna_2001, Chaleshtori_2005, Snoeckx_2005, Tsukada_2010, Primignani_2009). Although the phase of these variants was not explicitly specified in most studies, one report of the occurrence of these two variants in cis was ascertained (example, Primignani_2009). Therefore, the predominantly reported genotypes are considered as uninformative in the setting of autosomal recessive non syndromic hearing loss (ARNSHL). At-least one report of this variant in homozygosity in an individual from a cohort of ARNSHL was ascertained in this evaluation (Naddafnia_2018). Recently, a study evaluating this variant utilizing the hearing-loss-gene-specific criteria of the ClinGen Hearing Loss Expert Panel classified the variant as a VUS (example, Buonfiglio_2020). Overall, these data indicate that the variant may be associated with disease, but do not provide an unequivocal association with hearing loss. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on targeting to cell membrane, mean junctional and unitary conductance although an altered permeability to large cationic molecules such as ethidium bromide was reported (Mese_2008). However, the exact in-vivo consequences of these findings on the pathophysiology of hearing loss is not clear. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic, n=6; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as a VUS-possibly pathogenic. (less)
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Likely pathogenic
(Oct 01, 2021)
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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: SCV001148929.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455334.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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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GJB2 and GJB6 Genetic Variant Curation in an Argentinean Non-Syndromic Hearing-Impaired Cohort. | Buonfiglio P | Genes | 2020 | PMID: 33096615 |
Frequency of GJB2 mutations, GJB6-D13S1830 and GJB6-D13S1854 deletions among patients with non-syndromic hearing loss from the central region of Iran. | Naddafnia H | Molecular genetics & genomic medicine | 2019 | PMID: 31162818 |
Genetic mutations in non-syndromic deafness patients in Hainan Province have a different mutational spectrum compared to patients from Mainland China. | Huang B | International journal of pediatric otorhinolaryngology | 2018 | PMID: 29605365 |
Connexin 26 (GJB2) Mutations Associated with Non-Syndromic Hearing Loss (NSHL). | Mishra S | Indian journal of pediatrics | 2018 | PMID: 29542069 |
Application of SNPscan in Genetic Screening for Common Hearing Loss Genes. | Gao Z | PloS one | 2016 | PMID: 27792752 |
Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. | Burke WF | Hearing research | 2016 | PMID: 26778469 |
Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India. | Adhikary B | Gene | 2015 | PMID: 26188157 |
The Genetic Basis of Nonsyndromic Hearing Loss in Indian and Pakistani Populations. | Yan D | Genetic testing and molecular biomarkers | 2015 | PMID: 26186295 |
Carrier frequency of the GJB2 mutations that cause hereditary hearing loss in the Japanese population. | Taniguchi M | Journal of human genetics | 2015 | PMID: 26178431 |
Prevalence of Deafness-Associated Connexin-26 (GJB2) and Connexin-30 (GJB6) Pathogenic Alleles in a Large Patient Cohort from Eastern Sicily. | Amorini M | Annals of human genetics | 2015 | PMID: 26096904 |
Correlation analysis of phenotype and genotype of GJB2 in patients with non-syndromic hearing loss in China. | Dai ZY | Gene | 2015 | PMID: 26095810 |
NADf chip, a two-color microarray for simultaneous screening of multigene mutations associated with hearing impairment in North African Mediterranean countries. | Chakchouk I | The Journal of molecular diagnostics : JMD | 2015 | PMID: 25560255 |
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
Spectrum and frequency of GJB2 mutations causing deafness in the northwest of Iran. | Bonyadi MJ | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24529908 |
Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. | Dalamón V | Molecular biology reports | 2013 | PMID: 24158611 |
Simultaneous screening of multiple mutations by invader assay improves molecular diagnosis of hereditary hearing loss: a multicenter study. | Usami S | PloS one | 2012 | PMID: 22384008 |
Impaired membrane targeting and aberrant cellular localization of human Cx26 mutants associated with inherited recessive hearing loss. | Xiao Z | Acta oto-laryngologica | 2011 | PMID: 20863150 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss. | Primignani P | Genetic testing and molecular biomarkers | 2009 | PMID: 19371219 |
Connexin26 deafness associated mutations show altered permeability to large cationic molecules. | Meşe G | American journal of physiology. Cell physiology | 2008 | PMID: 18684989 |
Projection structure of a N-terminal deletion mutant of connexin 26 channel with decreased central pore density. | Oshima A | Cell communication & adhesion | 2008 | PMID: 18649181 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Prevalence of GJB2 mutations and the del(GJB6-D13S1830) in Argentinean non-syndromic deaf patients. | Dalamón V | Hearing research | 2005 | PMID: 15964725 |
Mutation analysis of the GJB2 (connexin 26) gene in Egypt. | Snoeckx RL | Human mutation | 2005 | PMID: 15954104 |
Connexin mutation testing of children with nonsyndromic, autosomal recessive sensorineural hearing loss. | Thomas MA | The Journal of otolaryngology | 2004 | PMID: 15841999 |
Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. | Meşe G | Human genetics | 2004 | PMID: 15241677 |
Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants. | Gasmelseed NMA | Human mutation | 2004 | PMID: 14722929 |
Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. | Wu BL | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172394 |
Connexin 26 studies in patients with sensorineural hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11556849 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8756501e-0855-4fe3-9e70-64b3569c122e | - | - | - | - |
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Text-mined citations for rs529500747 ...
HelpRecord last updated Apr 15, 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.