ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.269dup (p.Val91fs)
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.269dup (p.Val91fs)
Variation ID: 177737 Accession: VCV000177737.24
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189312-20189313 (GRCh38) [ NCBI UCSC ] 13: 20763451-20763452 (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 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.269dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Val91fs NM_004004.6:c.269dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.5:c.269dup NC_000013.11:g.20189313dup NC_000013.10:g.20763452dup NG_008358.1:g.8663dup LRG_1350:g.8663dup LRG_1350t1:c.269dup LRG_1350p1:p.Val91fs - Protein change
- V91fs
- Other names
- p.Val91SerfsX11
- Canonical SPDI
- NC_000013.11:20189312:A:AA
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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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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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Pathogenic (3) |
criteria provided, single submitter
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Jun 23, 2016 | RCV000154347.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2015 | RCV000211771.12 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 17, 2015 | RCV000678876.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV001052791.19 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257559.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 23, 2018 | RCV001270032.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2022 | RCV002492582.8 |
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
(Jun 23, 2016)
|
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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698240.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Variant summary: The GJB2 c.269dupT (p.Val91Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense … (more)
Variant summary: The GJB2 c.269dupT (p.Val91Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.290dupA, c.298delC, and c.313_326delAAGTTCATCAAGGG). This variant was observed in the large, broad control population, ExAC, with an allele frequency of 2/121348 (1/60674), which does not exceed the estimated maximal expected allele frequency for a pathogenic GJB2 variant of 1/40 (0.025). The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. (less)
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Pathogenic
(Apr 07, 2015)
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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: SCV000204010.4
First in ClinVar: Jan 31, 2015 Last updated: Jun 01, 2016 |
Comment:
The p.Val91fs (c.269_270insT) variant in GJB2 has been reported in over 10 indiv iduals with hearing loss who were homozygous or compound heterozygous for a … (more)
The p.Val91fs (c.269_270insT) variant in GJB2 has been reported in over 10 indiv iduals with hearing loss who were homozygous or compound heterozygous for a know n pathogenic variant (Dahl 2013, Dalamon 2013, Denoyelle 1999, Gravina 2010, Gre en 1999, Pandya 2003, Preciado 2004, Propst 2006, Siem 2010, Snoeckx 2005). Thi s variant has been identified in 2/66710 of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org); though this frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 91 and leads to a premature termination codon 11 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GJB2 gene is an establish ed disease mechanism in autosomal recessive sensorineural hearing loss. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal re cessive hearing loss based on predicted impact to the protein and prior reports of the variant in trans with a known pathogenic variant. ACMG/AMP Criteria appli ed: PVS1, PM3_VeryStrong, PM2. (less)
Number of individuals with the variant: 3
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Pathogenic
(Nov 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Deafness, nonsyndromic
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448745.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Apr 21, 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: SCV001825031.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 136 amino acids are lost and replaced with 10 incorrect amino … (more)
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 136 amino acids are lost and replaced with 10 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 33297549, 31589614, 33096615, 31160754, 10218527, 24158611) (less)
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Pathogenic
(Feb 24, 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: SCV002801640.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 18, 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: SCV001217017.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val91Serfs*11) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Val91Serfs*11) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 136 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs730880338, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with severe hearing loss and autosomal recessive deafness (PMID: 10218527, 11102979, 24158611). It has also been observed to segregate with disease in related individuals. This variant is also known as 269insT. ClinVar contains an entry for this variant (Variation ID: 177737). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 21, 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: SCV001434013.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frquency of c.269dup (p.Val91Serfs*11) variant in the GJB2 gene is 0,0012% … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frquency of c.269dup (p.Val91Serfs*11) variant in the GJB2 gene is 0,0012% (4/113654 european non-finnish chromosomes with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2 criteria. The c.269dup variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in trans with 35delG variant in at least 10 hearing loss patients (PMID: 102185257, 11102979, 11977173, 17146393, 20022641, 20553101, 23555729, 24158611) applying to PM3_VerySrong. The c.269dupT/35delG genotype segregated correctly in three affected siblings (Laboratory of Physiology and Genetics of Hearing, INGEBI internal data) meeting PP1_Moderate rule. Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PVS1, PM3_VerySrong, PP1_Moderate) (less)
Number of individuals with the variant: 3
Clinical Features:
Prelingual severe bilateral hearing loss (present)
Family history: yes
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Pathogenic
(Apr 14, 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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Revvity Omics, Revvity
Accession: SCV002024255.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 17, 2015)
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no assertion criteria provided
Method: clinical testing
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Hearing loss
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805069.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Pathogenic
(Mar 09, 2018)
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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: SCV000220877.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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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: SCV001453340.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Apr 27, 2023)
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no assertion criteria provided
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV004015005.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 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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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 |
Etiology and audiological outcomes at 3 years for 364 children in Australia. | Dahl HH | PloS one | 2013 | PMID: 23555729 |
GJB2 (Connexin 26) gene mutations among hearing-impaired persons in a Swedish cohort. | Carlsson PI | Acta oto-laryngologica | 2012 | PMID: 23039283 |
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 |
Causes of hearing impairment in the Norwegian paediatric cochlear implant program. | Siem G | International journal of audiology | 2010 | PMID: 20553101 |
Prevalence of DFNB1 mutations in Argentinean children with non-syndromic deafness. Report of a novel mutation in GJB2. | Gravina LP | International journal of pediatric otorhinolaryngology | 2010 | PMID: 20022641 |
Temporal bone imaging in GJB2 deafness. | Propst EJ | The Laryngoscope | 2006 | PMID: 17146393 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
A diagnostic paradigm for childhood idiopathic sensorineural hearing loss. | Preciado DA | Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2004 | PMID: 15577772 |
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 |
Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. | Pandya A | Genetics in medicine : official journal of the American College of Medical Genetics | 2003 | PMID: 12865758 |
Performance of cochlear implant recipients with GJB2-related deafness. | Green GE | American journal of medical genetics | 2002 | PMID: 11977173 |
Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). | Prasad S | Human mutation | 2000 | PMID: 11102979 |
Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. | Green GE | JAMA | 1999 | PMID: 10376574 |
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 |
Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. | Kelley PM | American journal of human genetics | 1998 | PMID: 9529365 |
- | - | - | - | PMID: 102185257 |
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Text-mined citations for rs730880338 ...
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.