ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.368C>A (p.Thr123Asn)
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.368C>A (p.Thr123Asn)
Variation ID: 44743 Accession: VCV000044743.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189214 (GRCh38) [ NCBI UCSC ] 13: 20763353 (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 Oct 2, 2016 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.368C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Thr123Asn missense NC_000013.11:g.20189214G>T NC_000013.10:g.20763353G>T NG_008358.1:g.8762C>A LRG_1350:g.8762C>A LRG_1350t1:c.368C>A LRG_1350p1:p.Thr123Asn P29033:p.Thr123Asn - Protein change
- T123N
- Other names
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- Canonical SPDI
- NC_000013.11:20189213:G:T
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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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0.00180 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00028
The Genome Aggregation Database (gnomAD), exomes 0.00051
Exome Aggregation Consortium (ExAC) 0.00055
1000 Genomes Project 30x 0.00172
1000 Genomes Project 0.00180
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
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. |
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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
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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Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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May 6, 2019 | RCV000037845.16 | |
Likely benign (2) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000281969.6 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000331479.5 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000590041.13 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV000785600.7 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 1, 2021 | RCV002477096.1 |
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
(Jun 10, 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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Eurofins Ntd Llc (ga)
Accession: SCV000342929.4
First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(-)
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criteria provided, single submitter
Method: research
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: yes
Allele origin:
unknown
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Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Accession: SCV000924177.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 1
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Likely benign
(Jun 09, 2011)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061507.5
First in ClinVar: May 03, 2013 Last updated: Dec 06, 2016 |
Comment:
Thr123Asn in exon 2 of GJB2: This variant has been previously reported in patien ts with hearing loss as well as in control subjects as … (more)
Thr123Asn in exon 2 of GJB2: This variant has been previously reported in patien ts with hearing loss as well as in control subjects as a rare polymorphism (Park 2000, Tang 2006, Cryns 2004, Dai 2009, Hwa 2003, Oguchi 2005, Ohtsuka 2003, Shi 2004, Snoeckx 2005). The allele frequencies of this variant are higher in the c ontrol group (~0.9%) than in the patient group (~0.4%), suggesting that this var iant does not have clinical significance. (less)
Number of individuals with the variant: 3
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Benign
(May 06, 2019)
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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: SCV000698253.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: GJB2 c.368C>A (p.Thr123Asn) results in a non-conservative amino acid change located in the central part of the cytoplasmic loop (CL) domain (Locke 2009) … (more)
Variant summary: GJB2 c.368C>A (p.Thr123Asn) results in a non-conservative amino acid change located in the central part of the cytoplasmic loop (CL) domain (Locke 2009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. One study indicates potential phosphorylation at this residue, however the functional significance of this post-translational modification is unknown (Locke 2009). The variant allele was found at a frequency of 0.00059 in 255584 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0065 in the gnomAD database, including 1 homozygote. This frequency is lower than the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025) (when considering autosomal recessive inheritance). However, in certain East Asian subpopulations even higher occurrences were reported e.g. in Koreans it was found at a frequency of 0.01 (gnomAD 2.1); that suggests the variant is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in multiple nonsyndromic sensorineural hearing loss (NSHL) patients (mainly East Asian ethnicity) without strong evidence for causality. The high occurrence in controls and the co-occurrence of other GJB2 disease variants in at least 2 patients argue against a potential dominant inheritance pattern (Dai 2009, Wu 2016). Many studies have reported the variant in patients with comparable frequencies (or lower than) detected in controls (e.g. Dai 2009, Nishio 2017), supporting the benign nature of this variant. A co-occurrence with a pathogenic variant (c.235delC) in trans was reported in a normal-hearing carrier (He 2017); further supporting a benign role for the variant. Though some studies raised the possibility that this variant can contribute to multigenic disorders, postulating that a combination of this variant with heterozygous alterations in other genes may be implicated in deafness (Chow 2017, Wu 2016), they provided no convincing evidence for the causative relationship. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of these laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Sep 01, 2021)
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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: SCV002797891.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Oct 22, 2020)
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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: SCV000969487.3
First in ClinVar: Aug 26, 2019 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 15504600, 19043807, 12792423, 15700112, 16380907, 12172394, 22613756, 12560944, 20497192, 31992338, 28900111, 19715472, 30245029, 25262649, 25266519, 10983956, … (more)
This variant is associated with the following publications: (PMID: 15504600, 19043807, 12792423, 15700112, 16380907, 12172394, 22613756, 12560944, 20497192, 31992338, 28900111, 19715472, 30245029, 25262649, 25266519, 10983956, 20607074, 19366456, 14985372, 23638949, 23826813, 17041943, 25388846, 22384008, 22695344, 25493717, 17666888, 20593197, 21162657) (less)
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Benign
(-)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000309915.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000383006.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000383008.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000383007.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Jan 29, 2024)
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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: SCV001083006.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Likely benign
(Apr 03, 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: SCV001453869.1
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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Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. | Azaiez H | American journal of human genetics | 2018 | PMID: 30245029 |
Carrier re-sequencing reveals rare but benign variants in recessive deafness genes. | He L | Scientific reports | 2017 | PMID: 28900111 |
Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family. | Chow YP | Orphanet journal of rare diseases | 2017 | PMID: 28222800 |
The Clinical Next-Generation Sequencing Database: A Tool for the Unified Management of Clinical Information and Genetic Variants to Accelerate Variant Pathogenicity Classification. | Nishio SY | Human mutation | 2017 | PMID: 28008688 |
Genetic and clinical analysis of nonsyndromic hearing impairment in pediatric and adult cases. | Xing J | Balkan journal of medical genetics : BJMG | 2016 | PMID: 27785406 |
Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic). | Barashkov NA | PloS one | 2016 | PMID: 27224056 |
Unraveling of Enigmatic Hearing-Impaired GJB2 Single Heterozygotes by Massive Parallel Sequencing: DFNB1 or Not? | Kim SY | Medicine | 2016 | PMID: 27057829 |
Application of a New Genetic Deafness Microarray for Detecting Mutations in the Deaf in China. | Wu H | PloS one | 2016 | PMID: 27018795 |
Correlation analysis of phenotype and genotype of GJB2 in patients with non-syndromic hearing loss in China. | Dai ZY | Gene | 2015 | PMID: 26095810 |
GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. | Zheng J | PloS one | 2015 | PMID: 26043044 |
Prevalence of mutations in GJB2, SLC26A4, and mtDNA in children with severe or profound sensorineural hearing loss in southwestern China. | Qing J | Genetic testing and molecular biomarkers | 2015 | PMID: 25493717 |
Comparative study of mutation spectrums of MT-RNR1 m.1555A>G, GJB2, and SLC26A4 between familial and sporadic patients with nonsyndromic sensorineural hearing loss in Chinese Han. | Li Q | Chinese medical journal | 2014 | PMID: 25266519 |
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. | Shearer AE | American journal of human genetics | 2014 | PMID: 25262649 |
Update of the spectrum of GJB2 mutations in 107 patients with nonsyndromic hearing loss in the Fujian population of China. | Chen T | Annals of human genetics | 2014 | PMID: 24645897 |
Spectrum and frequency of GJB2 mutations causing deafness in the northwest of Iran. | Bonyadi MJ | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24529908 |
Genetic mutations of GJB2 and mitochondrial 12S rRNA in nonsyndromic hearing loss in Jiangsu Province of China. | Wei Q | Journal of translational medicine | 2013 | PMID: 23826813 |
Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. | Yao G | Acta oto-laryngologica | 2013 | PMID: 23638949 |
The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study. | Bazazzadegan N | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22695344 |
Mutation detection in GJB2 gene among Malays with non-syndromic hearing loss. | Zainal SA | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22613756 |
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 |
Molecular epidemiological analysis of mitochondrial DNA12SrRNA A1555G, GJB2, and SLC26A4 mutations in sporadic outpatients with nonsyndromic sensorineural hearing loss in China. | Ji YB | Acta oto-laryngologica | 2011 | PMID: 21162657 |
Sequence Variations and Haplotypes of the GJB2 Gene Revealed by Resequencing of 192 Chromosomes from the General Population in Korea. | Kim HJ | Clinical and experimental otorhinolaryngology | 2010 | PMID: 20607074 |
Prospective variants screening of connexin genes in children with hearing impairment: genotype/phenotype correlation. | Yang JJ | Human genetics | 2010 | PMID: 20593197 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
Post-translational modifications of connexin26 revealed by mass spectrometry. | Locke D | The Biochemical journal | 2009 | PMID: 19775242 |
Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients. | Bonyadi M | Genetic testing and molecular biomarkers | 2009 | PMID: 19715472 |
GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. | Dai P | Journal of translational medicine | 2009 | PMID: 19366456 |
Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. | Han SH | Journal of human genetics | 2008 | PMID: 19043807 |
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 |
Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene. | Tekin M | American journal of medical genetics. Part A | 2007 | PMID: 17366579 |
DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. | Tang HY | American journal of medical genetics. Part A | 2006 | PMID: 17041943 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns. | Oguchi T | Journal of human genetics | 2005 | PMID: 15700112 |
GJB2 gene mutations in newborns with non-syndromic hearing impairment in Northern China. | Shi GZ | Hearing research | 2004 | PMID: 15504600 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. | Hwa HL | Genetics in medicine : official journal of the American College of Medical Genetics | 2003 | PMID: 12792423 |
GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. | Ohtsuka A | Human genetics | 2003 | PMID: 12560944 |
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 |
Connexin26 mutations associated with nonsyndromic hearing loss. | Park HJ | The Laryngoscope | 2000 | PMID: 10983956 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
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Text-mined citations for rs111033188 ...
HelpRecord last updated Mar 11, 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.