ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.1A>G (p.Met1Val)
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.1A>G (p.Met1Val)
Variation ID: 44729 Accession: VCV000044729.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189581 (GRCh38) [ NCBI UCSC ] 13: 20763720 (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 Mar 29, 2015 Apr 15, 2024 Mar 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Met1Val missense initiator codon variant NC_000013.11:g.20189581T>C NC_000013.10:g.20763720T>C NG_008358.1:g.8395A>G LRG_1350:g.8395A>G LRG_1350t1:c.1A>G LRG_1350p1:p.Met1Val - Protein change
- M1V
- Other names
- NM_004004.6(GJB2):c.1A>G
- p.Met1Val
- Canonical SPDI
- NC_000013.11:20189580:T:C
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00004
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
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
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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 (3) |
criteria provided, single submitter
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May 9, 2017 | RCV000037821.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2016 | RCV000211762.11 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000724654.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2022 | RCV000762907.10 | |
Pathogenic (1) |
reviewed by expert panel
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Mar 28, 2024 | RCV003990963.1 |
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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Pathogenic
(Mar 28, 2024)
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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: SCV004808382.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Comment:
The c.1A>G (p.Met1Val) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted … (more)
The c.1A>G (p.Met1Val) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 550716, 2070085, 371781, 551915). The highest population minor allele frequency of the variant is 0.02% (5/30616) in the South Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). Intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID: 12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID: 26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID: 20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID: 9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023). intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID: 12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID: 26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID: 20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID: 9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023). (less)
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Pathogenic
(May 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599721.2
First in ClinVar: Sep 19, 2017 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 22, 2021)
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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: SCV000603820.3
First in ClinVar: Jan 26, 2017 Last updated: Sep 03, 2023 |
Comment:
The GJB2 c.1A>G; p.Met1? variant has been described in the literature in individuals with autosomal recessive hearing loss as compound heterozygote with another GJB2 pathogenic … (more)
The GJB2 c.1A>G; p.Met1? variant has been described in the literature in individuals with autosomal recessive hearing loss as compound heterozygote with another GJB2 pathogenic variant or with a GJB6 pathogenic variant (Estivill 1998, Putcha 2007, Snoeckx 2005, Thonnissen 2002). This variant occurs in the initiation codon, the first methionine in the GJB2 protein, and has been shown to not produce a full-length functional protein (Thonnissen 2002). This variant is also reported in ClinVar (Variation ID: 44729). This variant is found in the general population with an overall allele frequency of 0.0036% (10/280566 alleles) in the Genome Aggregation Database. Therefore, this variant is considered pathogenic. References: Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7;351(9100):394-8. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Thönnissen E et al. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002 Aug;111(2):190-7. (less)
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Pathogenic
(Feb 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mutilating keratoderma
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Palmoplantar keratoderma-deafness syndrome Knuckle pads, deafness AND leukonychia syndrome Autosomal recessive nonsyndromic hearing loss 1A X-linked mixed hearing loss with perilymphatic gusher Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893317.3
First in ClinVar: Mar 31, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Mar 31, 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: SCV001795810.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 03, 2023 |
Comment:
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that c.1A>G is a null variant … (more)
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that c.1A>G is a null variant (Thonnissen et al., 2002); This variant is associated with the following publications: (PMID: 20146813, 29542069, 9482292, 16950989, 16380907, 20083784, 23695287, 23555729, 16532460, 15488970, 12910486, 10218527, 9710598, 18941476, 29625052, 33504652, 12189493, 18983339) (less)
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Pathogenic
(Mar 08, 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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Revvity Omics, Revvity
Accession: SCV002024268.4
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 19, 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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Invitae
Accession: SCV000932188.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in … (more)
This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs111033293, gnomAD 0.02%). Disruption of the initiator codon has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 9482292, 10218527, 18941476, 20146813). ClinVar contains an entry for this variant (Variation ID: 44729). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GJB2 function (PMID: 12189493). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2023)
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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: SCV004136782.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
GJB2: PM3:Very Strong, PM2, PVS1:Moderate
Number of individuals with the variant: 1
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Pathogenic
(Mar 01, 2017)
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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: SCV000700808.3
First in ClinVar: Sep 19, 2017 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Mar 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061483.6
First in ClinVar: May 03, 2013 Last updated: Sep 03, 2023 |
Comment:
The c.1A>G in GJB2 has been reported in at least 8 individuals with nonsyndromic hearing loss and segregated with disease in 1 family member (Estivill … (more)
The c.1A>G in GJB2 has been reported in at least 8 individuals with nonsyndromic hearing loss and segregated with disease in 1 family member (Estivill 1998, Tho nnissen 2002, Snoeckx 2005, Gardner 2006, Bajaj 2008). Many of these individuals were either homozygous or compound heterozygous. In addition, this variant has now been identified by our laboratory in 4 individuals with hearing loss who wer e also compound heterozygous for another pathogenic variant affecting the other copy of GJB2. This variant has been identified in 2/66508 European chromosomes i n the heterozygous state by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs111033293). It alters the start codon, and is there fore predicted to disrupt translation. An in vitro functional study provides som e evidence that that this variant might result in complete absence of protein (T honnissen 2002). In summary, this variant meets our criteria to be classified as pathogenic in an autosomal recessive manner. (less)
Number of individuals with the variant: 4
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Pathogenic
(Oct 12, 2016)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220945.3
First in ClinVar: Mar 29, 2015 Last updated: Sep 03, 2023 |
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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: SCV001455335.2
First in ClinVar: Jan 02, 2021 Last updated: Sep 03, 2023 |
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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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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 |
EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus. | Hoefsloot LH | European journal of human genetics : EJHG | 2013 | PMID: 23695287 |
Etiology and audiological outcomes at 3 years for 364 children in Australia. | Dahl HH | PloS one | 2013 | PMID: 23555729 |
High-throughput detection of mutations responsible for childhood hearing loss using resequencing microarrays. | Kothiyal P | BMC biotechnology | 2010 | PMID: 20146813 |
Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2010 | PMID: 20083784 |
Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. | Mani RS | European journal of human genetics : EJHG | 2009 | PMID: 18941476 |
Spectrum of GJB2 mutations causing deafness in the British Bangladeshi population. | Bajaj Y | Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery | 2008 | PMID: 18983339 |
A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. | Putcha GV | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17666888 |
Simultaneous multigene mutation detection in patients with sensorineural hearing loss through a novel diagnostic microarray: a new approach for newborn screening follow-up. | Gardner P | Pediatrics | 2006 | PMID: 16950989 |
Outcomes of clinical examination and genetic testing of 500 individuals with hearing loss evaluated through a genetics of hearing loss clinic. | Yaeger D | American journal of medical genetics. Part A | 2006 | PMID: 16532460 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Guidelines and recommendations for testing of Cx26 mutations and interpretation of results. | Mazzoli M | International journal of pediatric otorhinolaryngology | 2004 | PMID: 15488970 |
Use of a multiplex PCR/sequencing strategy to detect both connexin 30 (GJB6) 342 kb deletion and connexin 26 (GJB2) mutations in cases of childhood deafness. | Wu BL | American journal of medical genetics. Part A | 2003 | PMID: 12910486 |
Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. | Thönnissen E | Human genetics | 2002 | PMID: 12189493 |
Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. | Denoyelle F | Lancet (London, England) | 1999 | PMID: 10218527 |
Initiation of protein synthesis in mammalian cells with codons other than AUG and amino acids other than methionine. | Drabkin HJ | Molecular and cellular biology | 1998 | PMID: 9710598 |
Connexin-26 mutations in sporadic and inherited sensorineural deafness. | Estivill X | Lancet (London, England) | 1998 | PMID: 9482292 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b4129493-6f80-4264-8e10-ff56e3f3f128 | - | - | - | - |
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Text-mined citations for rs111033293 ...
HelpRecord last updated Apr 20, 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.