ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)
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.231G>A (p.Trp77Ter)
Variation ID: 17001 Accession: VCV000017001.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189351 (GRCh38) [ NCBI UCSC ] 13: 20763490 (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 Feb 14, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.231G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Trp77Ter nonsense NC_000013.11:g.20189351C>T NC_000013.10:g.20763490C>T NG_008358.1:g.8625G>A LRG_1350:g.8625G>A LRG_1350t1:c.231G>A LRG_1350p1:p.Trp77Ter - Protein change
- W77*
- Other names
- p.Trp77Ter
- Canonical SPDI
- NC_000013.11:20189350: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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0.00000 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00000
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00014
Exome Aggregation Consortium (ExAC) 0.00015
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 (5) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2023 | RCV000018524.39 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 22, 2017 | RCV000211767.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762904.2 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000711349.20 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004393.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001291332.1 | |
not provided (1) |
no classification provided
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- | RCV002286399.1 |
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
(May 08, 2018)
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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: SCV000841703.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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Pathogenic
(Jun 22, 2017)
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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: SCV000061488.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Trp77X variant in GJB2 has been reported in several individuals with heari ng loss who were either homozygous or compound heterozygous with a second … (more)
The p.Trp77X variant in GJB2 has been reported in several individuals with heari ng loss who were either homozygous or compound heterozygous with a second pathog enic variant in GJB2 (Kelsell 1997, Scott 1998, Rickard 2001, Santos 2005, Mani 2008, Padma 2009, Shafique 2014, LMM data). It has also been identified in 35/30 782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs80338944), which is consistent with the carrie r frequency for recessive hearing loss in the general population. This nonsense variant leads to a premature termination codon at position 77, which is predicte d to lead to a truncated protein. Loss of function of the GJB2 gene is an establ ished disease mechanism in autosomal recessive nonsyndromic hearing loss. In add ition, another nonsense variant at an adjacent nucleotide position (c.230G>A) re sulting in the same amino acid change has also been reported in many individuals with hearing loss (Hwa 2003, Bazazzagedan 2012, Huang 2015). Several individual s have been reported with the p.Trp77X variant; however, the nucleotide change w as not described (Cheng 2005, Bajaj 2008, Bhalla 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing l oss based upon the predicted impact of the variant, and homozygosity or compound heterozygosity in multiple affected individuals. (less)
Number of individuals with the variant: 4
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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 nonsyndromic hearing loss 1B
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163365.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(May 20, 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: SCV001812639.4
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22975760, 24949729, 19465004, 25087612, 25636251, 24840842, 9139825, 18941476, 29921236, 29542069, 29086887, 30168495, 20086291, 18983339, 31980526, 33614373) (less)
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Pathogenic
(Apr 04, 2023)
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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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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003922397.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A heterozygous nonsense variant in exon 2 of the GJB2 gene that results in a stop codon and premature truncation of the protein at codon … (more)
A heterozygous nonsense variant in exon 2 of the GJB2 gene that results in a stop codon and premature truncation of the protein at codon 77 (p.Trp77Ter) was detected. This variant has not been reported in 1000 genomes database and has a minor allele frequency of 0.004%, 0.01%, 0.0008% in the, gnomAD (v3.1), gnomdAD (v2), topmed and databases, respectively. The in silico prediction of the variant is damaging by MuttaionTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Hearing impairment (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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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
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013823.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). The variant is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33187236). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33187236). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017001 / PMID: 9139825 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Number of individuals with the variant: 2
Clinical Features:
Hearing impairment (present) , Severe hearing impairment (present) , Severe hearing impairment (present) , Hearing impairment (present) , Conductive hearing impairment (present) , Conductive hearing … (more)
Hearing impairment (present) , Severe hearing impairment (present) , Severe hearing impairment (present) , Hearing impairment (present) , Conductive hearing impairment (present) , Conductive hearing impairment (present) , Bilateral (present) (less)
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Pathogenic
(Oct 31, 2018)
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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: SCV000893314.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jun 19, 2018)
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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: SCV000917458.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: GJB2 c.231G>A (p.Trp77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GJB2 c.231G>A (p.Trp77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 246196 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00015 vs 0.025). c.231G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in homozygous and compound heterozygous state (e.g. Kelsell 1997, Santos 2005, Mani 2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024261.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 25, 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: SCV000936559.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp77*) 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.Trp77*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338944, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 9139825, 24840842, 25636251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17001). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Lys112Glufs*2) have been determined to be pathogenic (PMID: 9529365, 23141775). 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
(May 01, 1997)
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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: SCV000038806.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a large consanguineous family of Pakistani origin with recessive nonsyndromic profound deafness (DFNB1A; 220290) that mapped to 13q11-q12 (Brown et al., 1996), Kelsell et … (more)
In a large consanguineous family of Pakistani origin with recessive nonsyndromic profound deafness (DFNB1A; 220290) that mapped to 13q11-q12 (Brown et al., 1996), Kelsell et al. (1997) found that 2 affected individuals were homozygous for a G-to-A transition in the GJB2 gene, resulting in a trp77-to-ter (W77X) substitution. The parents were heterozygous for the mutation and had no noticeable hearing impairment. (less)
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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: SCV001453344.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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non-syndromic autosomal recessive hearing loss
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479806.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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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: SCV001958515.1 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
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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: SCV001976116.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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: SCV000041041.3
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 |
Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families. | Doll J | Genes | 2020 | PMID: 33187236 |
Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. | Richard EM | Human mutation | 2019 | PMID: 30303587 |
Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan. | Salman M | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2015 | PMID: 25636251 |
Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families. | Shafique S | PloS one | 2014 | PMID: 24949729 |
High incidence of GJB2 gene mutations among assortatively mating hearing impaired families in Kerala: future implications. | Pavithra A | Journal of genetics | 2014 | PMID: 24840842 |
A novel p.Leu213X mutation in GJB2 gene in a Portuguese family. | Gonçalves AC | International journal of pediatric otorhinolaryngology | 2013 | PMID: 23141775 |
GJB2 and GJB6 gene mutations found in Indian probands with congenital hearing impairment. | Padma G | Journal of genetics | 2009 | PMID: 20086291 |
Low incidence of GJB2, GJB6 and mitochondrial DNA mutations in North Indian patients with non-syndromic hearing impairment. | Bhalla S | Biochemical and biophysical research communications | 2009 | PMID: 19465004 |
Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. | Mani RS | European journal of human genetics : EJHG | 2009 | PMID: 18941476 |
Spectrum of GJB2 mutations causing deafness in the British Bangladeshi population. | Bajaj Y | Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery | 2008 | PMID: 18983339 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf. | Cheng X | American journal of medical genetics. Part A | 2005 | PMID: 16222667 |
Low prevalence of Connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment. | Santos RL | Clinical genetics | 2005 | PMID: 15617550 |
Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. | Hwa HL | Genetics in medicine : official journal of the American College of Medical Genetics | 2003 | PMID: 12792423 |
Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families. | Rickard S | Journal of medical genetics | 2001 | PMID: 11494963 |
Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. | Scott DA | Human mutation | 1998 | PMID: 9600457 |
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 |
Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations. | Carrasquillo MM | Human molecular genetics | 1997 | PMID: 9328482 |
Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. | Kelsell DP | Nature | 1997 | PMID: 9139825 |
Linkage studies of non-syndromic recessive deafness (NSRD) in a family originating from the Mirpur region of Pakistan maps DFNB1 centromeric to D13S175. | Brown KA | Human molecular genetics | 1996 | PMID: 8789457 |
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Text-mined citations for rs80338944 ...
HelpRecord last updated Mar 17, 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.