ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.95G>A (p.Arg32His)
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.95G>A (p.Arg32His)
Variation ID: 44766 Accession: VCV000044766.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189487 (GRCh38) [ NCBI UCSC ] 13: 20763626 (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 Jan 31, 2015 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.95G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Arg32His missense NC_000013.11:g.20189487C>T NC_000013.10:g.20763626C>T NG_008358.1:g.8489G>A LRG_1350:g.8489G>A LRG_1350t1:c.95G>A LRG_1350p1:p.Arg32His P29033:p.Arg32His - Protein change
- R32H
- Other names
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- Canonical SPDI
- NC_000013.11:20189486:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
569 | 636 |
Conditions - Germline
Condition
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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 (1) |
criteria provided, single submitter
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Jun 30, 2014 | RCV000037873.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2019 | RCV000410025.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2016 | RCV000411577.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV001218538.10 | |
Pathogenic (1) |
no assertion criteria provided
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May 14, 2020 | RCV001374640.1 | |
GJB2-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2023 | RCV004534808.1 |
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
(Nov 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360716.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GJB2 c.95G>A (p.Arg32His) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five … (more)
Variant summary: GJB2 c.95G>A (p.Arg32His) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250526 control chromosomes (gnomAD). c.95G>A has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Baux_2017, Marlin_2001, Mustapha_2001, Snoeckx_2005). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects gap junction functions by causing impaired membrane targeting and aberrant cellular localization (Xiao_2011). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 03, 2016)
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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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Counsyl
Accession: SCV000487687.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Aug 03, 2016)
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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:
unknown
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Counsyl
Accession: SCV000487688.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 25, 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: SCV001781650.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest a damaging effect on protein localization as the mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011) and … (more)
Published functional studies suggest a damaging effect on protein localization as the mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011) and fails to form gap junction plaques (Beach et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31162818, 25388846, 29501291, 15070423, 31589614, 20863150, 11493200, 33105617, 31160754, 27792752, 32300592) (less)
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Pathogenic
(Jul 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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GJB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120433.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GJB2 c.95G>A variant is predicted to result in the amino acid substitution p.Arg32His. This variant has been reported in the homozygous and compound heterozygous … (more)
The GJB2 c.95G>A variant is predicted to result in the amino acid substitution p.Arg32His. This variant has been reported in the homozygous and compound heterozygous states along with GJB2 premature termination variants in multiple individuals with non-syndromic hearing loss (Table 2, Marlin. 2001. PubMed ID: 11493200; Table 1, Santos. 2005. PubMed ID: 15617550; Table 2, Xia. 2016. PubMed ID: 27045574; Table 3, Gao. 2016. PubMed ID: 27792752). In vitro experimental studies suggest this variant impairs normal localization to the cell surface and may lead to premature protein degradation (Xiao. 2010. PubMed ID: 20863150; Beach. 2020. PubMed ID: 32300592). Other substitutions (Cys, Leu) at the same amino acid position have been classified as pathogenic at PreventionGenetics. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763626-C-T). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Nov 27, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001390424.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 32 of the GJB2 protein (p.Arg32His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 32 of the GJB2 protein (p.Arg32His). This variant is present in population databases (rs111033190, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 11493200, 15666300, 29501291). ClinVar contains an entry for this variant (Variation ID: 44766). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 20863150). This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11102979, 19371219, 21465647, 26346709, 27045574). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 30, 2014)
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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: SCV000061535.5
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
The Arg32His variant in GJB2 has been reported in many probands with sensorineur al hearing loss (Wajid 2004, Chaleshtori 2005, Pollak 2007, Bonyadi 2009, Feldm … (more)
The Arg32His variant in GJB2 has been reported in many probands with sensorineur al hearing loss (Wajid 2004, Chaleshtori 2005, Pollak 2007, Bonyadi 2009, Feldm ann 2004, Hamid 2009, Marlin 2005, Marlin 2001, Mustapha 2001, Najmabadi 2005, P utcha 2007, Roux 2004, Santos 2005, Siemering 2006, Snoeckx 2005). At least 15 o f these probands were homozygous or compound heterozygous. In summary, this vari ant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org /LMM). (less)
Number of individuals with the variant: 3
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047951.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The GJB2 (c.95G>A) variant has been reported in multiple individuals affected with Deafness, autosomal recessive 1A (Naddafnia et. al., 2019; Roux et. al., 2004). Published … (more)
The GJB2 (c.95G>A) variant has been reported in multiple individuals affected with Deafness, autosomal recessive 1A (Naddafnia et. al., 2019; Roux et. al., 2004). Published functional studies suggest a damaging effect on protein localization as the mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011). The p.Arg32His variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg32His in GJB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. The amino acid Arg at position 32 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant /CNV in GJB2 gene, the molecular diagnosis is not confirmed. (less)
Clinical Features:
Hearing impairment (present) , Dyspnea (present)
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Pathogenic
(May 14, 2020)
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no assertion criteria provided
Method: clinical testing
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nonsyndromic sensorineural hearing loss
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV001571558.1
First in ClinVar: Apr 24, 2021 Last updated: Apr 24, 2021 |
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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: SCV001453358.1
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 mutations causing autosomal recessive non-syndromic hearing loss (ARNSHL) in two Iranian populations: Report of two novel variants. | Koohiyan M | International journal of pediatric otorhinolaryngology | 2018 | PMID: 29501291 |
Combined genetic approaches yield a 48% diagnostic rate in a large cohort of French hearing-impaired patients. | Baux D | Scientific reports | 2017 | PMID: 29196752 |
Compound heterozygous GJB2 mutations associated to a consanguineous Han family with autosomal recessive non-syndromic hearing loss. | Xia H | Acta oto-laryngologica | 2016 | PMID: 27045574 |
A Mayan founder mutation is a common cause of deafness in Guatemala. | Carranza C | Clinical genetics | 2016 | PMID: 26346709 |
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
Mutation detection in GJB2 gene among Malays with non-syndromic hearing loss. | Zainal SA | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22613756 |
Vestibular dysfunction in DFNB1 deafness. | Dodson KM | American journal of medical genetics. Part A | 2011 | PMID: 21465647 |
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 novel 355-357delGAG mutation and frequency of connexin-26 (GJB2) mutations in Iranian patients. | Hamid M | Journal of genetics | 2009 | PMID: 20086306 |
Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients. | Bonyadi M | Genetic testing and molecular biomarkers | 2009 | PMID: 19715472 |
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 |
M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. | Pollak A | American journal of medical genetics. Part A | 2007 | PMID: 17935238 |
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 |
Detection of mutations in genes associated with hearing loss using a microarray-based approach. | Siemering K | The Journal of molecular diagnostics : JMD | 2006 | PMID: 16931589 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. | Marlin S | Archives of otolaryngology--head & neck surgery | 2005 | PMID: 15967879 |
GJB2 mutations: passage through Iran. | Najmabadi H | American journal of medical genetics. Part A | 2005 | PMID: 15666300 |
Low prevalence of Connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment. | Santos RL | Clinical genetics | 2005 | PMID: 15617550 |
GJB2: the spectrum of deafness-causing allele variants and their phenotype. | Azaiez H | Human mutation | 2004 | PMID: 15365987 |
Large deletion of the GJB6 gene in deaf patients heterozygous for the GJB2 gene mutation: genotypic and phenotypic analysis. | Feldmann D | American journal of medical genetics. Part A | 2004 | PMID: 15150777 |
Molecular epidemiology of DFNB1 deafness in France. | Roux AF | BMC medical genetics | 2004 | PMID: 15070423 |
Autosomal recessive non-syndromic hearing loss in the Lebanese population: prevalence of the 30delG mutation and report of two novel mutations in the connexin 26 (GJB2) gene. | Mustapha M | Journal of medical genetics | 2001 | PMID: 11584050 |
Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. | Marlin S | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11493200 |
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 |
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Text-mined citations for rs111033190 ...
HelpRecord last updated Oct 13, 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.