ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)
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.427C>T (p.Arg143Trp)
Variation ID: 17009 Accession: VCV000017009.76
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189155 (GRCh38) [ NCBI UCSC ] 13: 20763294 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 3, 2013 Apr 20, 2024 Feb 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.427C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Arg143Trp missense NC_000013.11:g.20189155G>A NC_000013.10:g.20763294G>A NG_008358.1:g.8821C>T LRG_1350:g.8821C>T LRG_1350t1:c.427C>T LRG_1350p1:p.Arg143Trp P29033:p.Arg143Trp - Protein change
- R143W
- Other names
- -
- Canonical SPDI
- NC_000013.11:20189154:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00021
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00017
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00025
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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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Dec 24, 2019 | RCV000018533.47 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000146023.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 14, 2019 | RCV000211779.14 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000255157.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2021 | RCV000515418.11 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 2, 2014 | RCV000678885.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 10, 2021 | RCV001027826.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257564.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2016 | RCV001196233.10 | |
not provided (1) |
no classification provided
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- | RCV002286400.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 3, 2024 | RCV003407345.5 | |
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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
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193175.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Apr 21, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698257.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Comment:
Variant summary: The c.427C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Arg to Trp. 5/5 in-silico tools predict damaging outcome for … (more)
Variant summary: The c.427C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Arg to Trp. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 20/121442 control chromosomes at a frequency of 0.0001647, which does not exceed maximal expected frequency of a pathogenic allele (0.025). The variant of interest has been reported to be a common pathogenic variant predominantly found in Ghana (Hamelmann_2001). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. (less)
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Pathogenic
(Mar 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV001143669.1
First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found … (more)
The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. (less)
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366784.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic.
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Pathogenic
(Apr 08, 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: SCV001473072.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 08, 2022 |
Comment:
The GJB2 c.427C>T; p.Arg143Trp variant (rs80338948) is a well-studied pathogenic variant associated with autosomal recessive deafness-1A (DFNB1A) and has been observed in affected individuals both … (more)
The GJB2 c.427C>T; p.Arg143Trp variant (rs80338948) is a well-studied pathogenic variant associated with autosomal recessive deafness-1A (DFNB1A) and has been observed in affected individuals both in the homozygous state and in trans to other pathogenic GJB2 variants (Abe 2018, Brobby 1998, Dodson 2011, Sloan-Heggen 2016). This variant is found in the African population with an overall allele frequency of 0.07% (18/24908 alleles) in the Genome Aggregation Database, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17009). The arginine at codon 143 is highly conserved, and while conclusions from functional studies are somewhat varied, functional assays indicate that the p.Arg143Trp variant inhibits gap junction formation and reduced conductance (Wang 2003, Mese 2004, Palmada 2006). Additionally, other amino acid substitutions at this codon (p.Arg143Gln, p.Arg143Leu) have been reported in individuals with hearing loss and are considered disease-causing (Loffler 2001, Putcha 2007). Based on available information, the p.Arg143Trp variant is considered to be pathogenic. References: Abe S et al. Diagnostic pitfalls for GJB2-related hearing loss: A novel deletion detected by Array-CGH analysis in a Japanese patient with congenital profound hearing loss. Clin Case Rep. 2018 Sep 21;6(11):2111-2116. Brobby et al. Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa. N Engl J Med. 1998; 338(8): 548-550. Dodson et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011; 155A(5): 993-1000. Loffler J et al. Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. Eur J Hum Genet. 2001 Mar;9(3):226-30. Mese et al. Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum Genet. 2004; 115(3): 191-199. Palmada et al. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006; 22(1): 112-118. 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. Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016; 135(4): 441-450. Wang et al. Functional analysis of connexin-26 mutants associated with hereditary recessive deafness. J Neurochem. 2003; 84(4): 735-742. (less)
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Pathogenic
(Aug 03, 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: SCV000611272.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 08, 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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GeneDx
Accession: SCV000322424.12
First in ClinVar: Oct 09, 2016 Last updated: Sep 22, 2023 |
Comment:
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: 16300957, … (more)
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: 16300957, 25388846, 30455902, 34943631, 25087612, 12833397, 21465647, 25266519, 15241677, 12562518, 9471561, 19043807, 31370293, 31162818, 30146550, 32012697, 9393973, 15235031, 31541171, 31160754, 30275481, 32645618, 33597575, 33096615, 31589614, 29871260, 33297549, 32067424, 36147510, 34599368, 35114279, 35336849, 36493725, 35982127) (less)
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Pathogenic
(Mar 28, 2022)
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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: SCV002024270.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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: SCV000939977.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the GJB2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the GJB2 protein (p.Arg143Trp). This variant is present in population databases (rs80338948, gnomAD 0.07%). This missense change has been observed in individuals with hearing loss (PMID: 15365987, 15617546, 18941476, 19715472, 23638949, 26061264, 27792752). ClinVar contains an entry for this variant (Variation ID: 17009). 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: 9393973, 15235031). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 03, 2024)
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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: SCV004116141.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The GJB2 c.427C>T variant is predicted to result in the amino acid substitution p.Arg143Trp. This variant was reported in an individual with autosomal recessive nonsyndromic … (more)
The GJB2 c.427C>T variant is predicted to result in the amino acid substitution p.Arg143Trp. This variant was reported in an individual with autosomal recessive nonsyndromic hearing loss (Brobby et al 1998. PubMed ID: 9471561; Maheshwari et al. 2003. PubMed ID: 12833397; Abe et al. 2018. PubMed ID: 30455902). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. (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: no, yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599751.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Number of individuals with the variant: 1
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Pathogenic
(May 15, 2015)
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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: SCV000227320.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(Dec 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193995.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
NM_004004.5(GJB2):c.427C>T(R143W) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 11439000, … (more)
NM_004004.5(GJB2):c.427C>T(R143W) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 11439000, 12562518, 15241677 and 16300957. Classification of NM_004004.5(GJB2):c.427C>T(R143W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã (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: SCV001434018.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.427C>T, p.Arg143Trp variant in GBJ2 gene is 0,04% … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.427C>T, p.Arg143Trp variant in GBJ2 gene is 0,04% (18/24908 African chromosomes with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria. The p.Arg143Trp change was identified in trans with at least 7 known pathogenic variants applying to PM3_VeryStrong rule(PMID: 9471561, 14985372, 10633133, 11556849, 10982180, 24158611). In one family this variant was identified in trans with a reported pathogenic variant and segregated among family members applying to PP1_Supporting criteria (PMID: 10633133). Computational analysis predicted a pathogenic impact of the mutation to the protein (REVEL=0.918; PP3). Functional studies demonstrated that p.Arg143Trp mutant formed functional channels that were permeable to fluorescent tracers in transfected N2A cells and conductance levels measured similar to that of WT-Cx26 (PMID: 12562518). However, it did not induce the formation of functional GJCh in paired Xenopus laevis oocytes (PMID: 15241677, 16300957). As the evidence is contradictory functional data was not counted. In summary, This variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PM3_VeryStrong, PP1_Supporting and PP3. (less)
Observation 1:
Number of individuals with the variant: 5
Clinical Features:
Prelingual severe to profound bilateral hearing loss (present)
Family history: yes
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Prelingual profound bilateral hearing loss (present)
Family history: no
Sex: male
Ethnicity/Population group: Latino
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Pathogenic
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784259.2
First in ClinVar: Sep 19, 2017 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 20-29 years
Sex: female
Geographic origin: Iran
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Pathogenic
(Dec 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma-deafness syndrome
Autosomal recessive nonsyndromic hearing loss 1A Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss Knuckle pads, deafness AND leukonychia syndrome Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Mutilating keratoderma
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001190446.2
First in ClinVar: Mar 26, 2020 Last updated: May 06, 2023 |
Comment:
GJB2 NM_004004.5 exon 2 p.Arg143Trp (c.427C>T): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with … (more)
GJB2 NM_004004.5 exon 2 p.Arg143Trp (c.427C>T): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with nonsyndromic hearing loss, segregating with disease in multiple affected family members (Brobby 1998 PMID:9471561, Abe 2000 PMID:10633133, Maheshwari 2003 PMID:12833397, Cryns 2004 PMID:14985372, Kenna 2010 PMID:20083784, Dodson 2011 PMID:21465647, Abe 2018 PMID:30455902). This variant is present in 0.07% (18/24908) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-20763294-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17009). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies have shown that this mutant protein is unable to from functional channels (Palmada 2006 PMID:16300957). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above (segregation studies, impact to protein etc.). (less)
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Pathogenic
(May 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061515.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Arg143Trp variant in GJB2 has been reported in many probands with hearing loss (Brobby 1998, Abe 2000, Rabionet 2000, Kenna 2001, Cryns 2004, Chaleshtori … (more)
The p.Arg143Trp variant in GJB2 has been reported in many probands with hearing loss (Brobby 1998, Abe 2000, Rabionet 2000, Kenna 2001, Cryns 2004, Chaleshtori 2005, Snoeckx 2005, LMM data). Most of these probands were homozygous or compound heterozygous. It has also been identified in 0.07% (18/24908) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency for autosomal recessive nonsyndromic hearing loss. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies support an impact on protein function (Mese 2004, Palmada 2006). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Supporting, PP3. (less)
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Pathogenic
(Dec 01, 2002)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 1A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038815.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a village in eastern Ghana known for having an extraordinarily high prevalence of profound nonsyndromic hearing impairment (220290), Brobby et al. (1998) found that … (more)
In a village in eastern Ghana known for having an extraordinarily high prevalence of profound nonsyndromic hearing impairment (220290), Brobby et al. (1998) found that 21 deaf subjects from 11 families were homozygous for a C-to-T transition in the GJB2 gene that resulted in a nonconservative arg143-to-trp (R143W) amino acid exchange. All heterozygous family members had normal hearing. In the families studied in Ghana, the disease haplotypes differed greatly among families, indicating that the mutation arose at least 60 generations ago and that the village community has been highly stable. Meyer et al. (2002) raised the possibility that the R143W mutation may have some selective advantage. They noted that CX26 is expressed not only in the inner ear but also in the embryonic epidermis, palmoplantar epidermis, sweat glands, and other tissues. They found that the epidermis was significantly thicker in individuals heterozygous or homozygous for the R143W mutation than in wildtype family members. Moreover, whereas sweat volumes were similar, sodium and chloride concentrations in sweat were higher among homozygotes than in other groups. Functionally, these changes were considered to be compatible with an unfavorable osmotic milieu for microbial colonization and a more robust mechanical skin barrier against pathogen invasion, trauma, and insect bites. (less)
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Pathogenic
(Oct 02, 2014)
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no assertion criteria provided
Method: clinical testing
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Hearing loss
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805078.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956935.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964498.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: case-control
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
inherited
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902311.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 1
Clinical Features:
hearing loss (present)
Family history: yes
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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: SCV001463369.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041048.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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-Related Autosomal Recessive Nonsyndromic Hearing Loss. | Adam MP | - | 2023 | PMID: 20301449 |
Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis. | Shen N | Oncotarget | 2017 | PMID: 28489599 |
WFS1 and GJB2 mutations in patients with bilateral low-frequency sensorineural hearing loss. | Kasakura-Kimura N | The Laryngoscope | 2017 | PMID: 28271504 |
Application of SNPscan in Genetic Screening for Common Hearing Loss Genes. | Gao Z | PloS one | 2016 | PMID: 27792752 |
Unraveling of Enigmatic Hearing-Impaired GJB2 Single Heterozygotes by Massive Parallel Sequencing: DFNB1 or Not? | Kim SY | Medicine | 2016 | PMID: 27057829 |
Cordblood-Based High-Throughput Screening for Deafness Gene of 646 Newborns in Jinan Area of China. | Li SX | Clinical and experimental otorhinolaryngology | 2015 | PMID: 26330914 |
Carrier frequency of the GJB2 mutations that cause hereditary hearing loss in the Japanese population. | Taniguchi M | Journal of human genetics | 2015 | PMID: 26178431 |
Correlation analysis of phenotype and genotype of GJB2 in patients with non-syndromic hearing loss in China. | Dai ZY | Gene | 2015 | PMID: 26095810 |
Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population. | Kim SY | PloS one | 2015 | PMID: 26061264 |
GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. | Zheng J | PloS one | 2015 | PMID: 26043044 |
GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. | Hernández-Juárez AA | International journal of pediatric otorhinolaryngology | 2014 | PMID: 25288386 |
Frequency of GJB2 and del(GJB6-D13S1830) mutations among an Ecuadorian mestizo population. | Paz-y-Miño C | International journal of pediatric otorhinolaryngology | 2014 | PMID: 25085072 |
Prevalence of GJB2 mutations in the Silk Road region of China and a report of three novel variants. | Du W | Acta oto-laryngologica | 2014 | PMID: 24256046 |
GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. | Chan DK | The Laryngoscope | 2014 | PMID: 23900770 |
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 |
Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. | Yao G | Acta oto-laryngologica | 2013 | PMID: 23638949 |
Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity. | Kim SY | PloS one | 2013 | PMID: 23637863 |
Long term speech perception after cochlear implant in pediatric patients with GJB2 mutations. | Yoshida H | Auris, nasus, larynx | 2013 | PMID: 23477838 |
Genetic Screening of GJB2 and SLC26A4 in Korean Cochlear Implantees: Experience of Soree Ear Clinic. | Shin JW | Clinical and experimental otorhinolaryngology | 2012 | PMID: 22701767 |
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 |
Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutation in Belarus. | Danilenko N | PloS one | 2012 | PMID: 22567152 |
Comorbidity of GJB2 and WFS1 mutations in one family. | Minami SB | Gene | 2012 | PMID: 22498363 |
Vestibular dysfunction in DFNB1 deafness. | Dodson KM | American journal of medical genetics. Part A | 2011 | PMID: 21465647 |
Prevalence of GJB2 causing recessive profound non-syndromic deafness in Japanese children. | Hayashi C | International journal of pediatric otorhinolaryngology | 2011 | PMID: 21112098 |
Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia. | Teek R | International journal of pediatric otorhinolaryngology | 2010 | PMID: 20708129 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
GJB2 mutation spectrum in 209 hearing impaired individuals of predominantly Caribbean Hispanic and African descent. | Shan J | International journal of pediatric otorhinolaryngology | 2010 | PMID: 20381175 |
GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf. | Tekin M | Annals of human genetics | 2010 | PMID: 20201936 |
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 |
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 |
GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. | Dai P | Journal of translational medicine | 2009 | PMID: 19366456 |
Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. | Mani RS | European journal of human genetics : EJHG | 2009 | PMID: 18941476 |
Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. | Han SH | Journal of human genetics | 2008 | PMID: 19043807 |
A deafness-associated mutant human connexin 26 improves the epithelial barrier in vitro. | Man YK | The Journal of membrane biology | 2007 | PMID: 17581693 |
GJB2 and GJB6 mutations in children with congenital cytomegalovirus infection. | Ross SA | Pediatric research | 2007 | PMID: 17426645 |
Effects of GJB2 genotypes on the audiological phenotype: variability is present for all genotypes. | Hişmi BO | International journal of pediatric otorhinolaryngology | 2006 | PMID: 16712961 |
Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. | Palmada M | Neurobiology of disease | 2006 | PMID: 16300957 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Mutation analysis of the GJB2 (connexin 26) gene in Egypt. | Snoeckx RL | Human mutation | 2005 | PMID: 15954104 |
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 |
Evidence for single origins of 35delG and delE120 mutations in the GJB2 gene in Anatolia. | Tekin M | Clinical genetics | 2005 | PMID: 15617546 |
GJB2: the spectrum of deafness-causing allele variants and their phenotype. | Azaiez H | Human mutation | 2004 | PMID: 15365987 |
Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. | Meşe G | Human genetics | 2004 | PMID: 15241677 |
Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival. | Common JE | Journal of medical genetics | 2004 | PMID: 15235031 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants. | Gasmelseed NMA | Human mutation | 2004 | PMID: 14722929 |
Screening of families with autosomal recessive non-syndromic hearing impairment (ARNSHI) for mutations in GJB2 gene: Indian scenario. | Maheshwari M | American journal of medical genetics. Part A | 2003 | PMID: 12833397 |
Functional analysis of connexin-26 mutants associated with hereditary recessive deafness. | Wang HL | Journal of neurochemistry | 2003 | PMID: 12562518 |
GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. | Ohtsuka A | Human genetics | 2003 | PMID: 12560944 |
Selection for deafness? | Meyer CG | Nature medicine | 2002 | PMID: 12457154 |
GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. | Kenneson A | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172392 |
High-throughput screening for GJB2 mutations--its clinical application to genetic testing in prelingual deafness screening for GJB2 mutations. | Sugata A | Auris, nasus, larynx | 2002 | PMID: 12167443 |
Deafness resulting from mutations in the GJB2 (connexin 26) gene in Brazilian patients. | Oliveira CA | Clinical genetics | 2002 | PMID: 12081719 |
Better speech performance in cochlear implant patients with GJB2-related deafness. | Fukushima K | International journal of pediatric otorhinolaryngology | 2002 | PMID: 11788148 |
Connexin 26 studies in patients with sensorineural hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11556849 |
Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. | Hamelmann C | Human mutation | 2001 | PMID: 11439000 |
Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. | Rabionet R | Human genetics | 2000 | PMID: 10982180 |
Prevalent connexin 26 gene (GJB2) mutations in Japanese. | Abe S | Journal of medical genetics | 2000 | PMID: 10633133 |
Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa. | Brobby GW | The New England journal of medicine | 1998 | PMID: 9471561 |
Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes. | Duflot-Dancer A | Oncogene | 1997 | PMID: 9393973 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
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Text-mined citations for rs80338948 ...
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.