ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.283G>A (p.Val95Met)
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.283G>A (p.Val95Met)
Variation ID: 44735 Accession: VCV000044735.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189299 (GRCh38) [ NCBI UCSC ] 13: 20763438 (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 Nov 23, 2014 Mar 10, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.283G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Val95Met missense NC_000013.11:g.20189299C>T NC_000013.10:g.20763438C>T NG_008358.1:g.8677G>A LRG_1350:g.8677G>A LRG_1350t1:c.283G>A LRG_1350p1:p.Val95Met P29033:p.Val95Met - Protein change
- V95M
- Other names
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- Canonical SPDI
- NC_000013.11:20189298: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00008
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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 | 619 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2020 | RCV000037834.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000146014.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2017 | RCV000211719.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515247.3 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000516830.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257560.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2022 | RCV002228125.2 |
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
(Aug 26, 2016)
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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: SCV000613510.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Feb 09, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603835.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The GJB2 c.283G>A; p.Val95Met variant has been reported multiple times in the literature in individuals and families with hearing loss who were compound heterozygous with … (more)
The GJB2 c.283G>A; p.Val95Met variant has been reported multiple times in the literature in individuals and families with hearing loss who were compound heterozygous with another pathogenic variant (Cheng 2005, Kelley 1998, Oliveira 2002, Putcha 2007, Snoeckx 2005). Additionally, functional studies suggest the variant protein affects biochemical coupling, but has little or no effect on intercellular conductance of gap junctions (Zhang 2005, Wang 2003). This variant has been reported to the ClinVar database (Variation ID: 44735), and is observed in the general population databases at a frequency of 0.005% (rs111033299, Genome Aggregation Database). The valine at codon 95 is well conserved across species, and computational algorithms predict this variant to be damaging to the protein (SIFT, PolyPhen2, MutationTaster). Taken together, this variant is considered pathogenic. (less)
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Pathogenic
(Aug 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001434014.1
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 filter allele sequence of the c.283G>A p.(Val95Met) in GJB2 gene is 0,0056% (5/34590 … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele sequence of the c.283G>A p.(Val95Met) in GJB2 gene is 0,0056% (5/34590 alleles in Latino population with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), meeting PM2 criteria. This variant was identified in trans with several pathogenic variants in at least 10 patients with non-syndromic hearing loss (PM3_VeryStrong; PMID: 9529365, 11216656, 12081719, 12239718, 14985372, 15967879, 16380907, 20234132, 26043044, 24158611). This change in trans with pathogenic variants segregated in two siblings in two different families applying to PP1_Supporting (PMID:9529365, 11216656). Computational evidence predicted a pathogenic effect of the variant to the protein (REVELscore: 0.894; PP3). Functional studies showed that V95M mutant formed functional channels that were permeable to fluorescent tracers in transfected N2A cells and conductance measure similar to WT-Cx26. However, reduce permeability to larger molecules was demonstrated (PMID: 12562518, 16217030). Therefore, functional data was not counted. Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PM3_VeryStrong, PP1_Supporting and PP3) (less)
Observation 1:
Number of individuals with the variant: 2
Clinical Features:
Prelingual moderate bilateral hearing loss (present)
Family history: yes
Sex: male
Ethnicity/Population group: Mapuche
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: female
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Pathogenic
(Jul 10, 2020)
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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:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001761051.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
Clinical Features:
Intellectual disability (present) , Seizure (present) , Thin vermilion border (present) , Microcephaly (present) , Epicanthus (present) , High palate (present) , Bilateral sensorineural hearing … (more)
Intellectual disability (present) , Seizure (present) , Thin vermilion border (present) , Microcephaly (present) , Epicanthus (present) , High palate (present) , Bilateral sensorineural hearing impairment (present) , Generalized hypotonia (present) , Hypothyroidism (present) , Absent speech (present) , Asthma (present) (less)
Secondary finding: no
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Likely pathogenic
(Nov 07, 2014)
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criteria provided, single submitter
Method: literature only
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Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220868.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 09, 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: SCV001871336.4
First in ClinVar: Sep 19, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on the ion permeability of gap junction channels formed by the mutant GJB2 protein (Zhang et al., 2005); … (more)
Published functional studies demonstrate a damaging effect on the ion permeability of gap junction channels formed by the mutant GJB2 protein (Zhang et al., 2005); 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: 11439000, 22695344, 12325027, 19887791, 17567887, 21465647, 26117665, 16125251, 25388846, 11102979, 20234132, 12562518, 9529365, 15967879, 12239718, 16222667, 27792752, 18983339, 12081719, 14985372, 16380907, 23668481, 25401782, 11134236, 19371219, 17041943, 15365987, 15150777, 19235794, 26043044, 11216656, 16931589, 22613756, 24256046, 27843504, 24156272, 30609409, 30168495, 31370293, 31160754, 16217030, 33096615, 31589614, 29871260, 34308104, 34599368) (less)
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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: SCV000193165.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(May 18, 2017)
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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: SCV000611270.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Pathogenic
(May 02, 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: SCV000061496.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Val95Met variant in GJB2 has been reported in the compound heterozygous st ate in at least 19 individuals with hearing loss and segregated in … (more)
The p.Val95Met variant in GJB2 has been reported in the compound heterozygous st ate in at least 19 individuals with hearing loss and segregated in at least thre e affected relatives (Cheng 2005, Cryns 2004, Kelley 1998, Lemonnier 1990, Marli n 2005, Oliveira 2002, Pandya 2003, Wang 2003, LMM data). This variant has been identified in multiple ethnic groups with a highest frequency of 5/33580 of Lati no chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs111033299). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a carrier freq uency for autosomal recessive nonsyndromic hearing loss. In summary, this varian t meets criteria to be classified as pathogenic for nonsyndromic hearing loss in an autosomal recessive manner based upon biallelic observations in affected ind ividuals, segregation evidence, and low frequency in the general population. ACM G/AMP Criteria applied: PP1, PP3, PM2, PM3_VS. (less)
Number of individuals with the variant: 8
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Pathogenic
(Apr 27, 2022)
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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: SCV002511670.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: GJB2 c.283G>A (p.Val95Met) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four … (more)
Variant summary: GJB2 c.283G>A (p.Val95Met) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251540 control chromosomes (gnomAD, Cheng_2005, Kelley_1998). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.283G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Castro_2013, Cheng_2005, Cryns_2004, Kelley_1998, Dalamon_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports that the variant negatively impacted large molecule trafficking across gap junctions, thereby disrupting gap junction mediated intracellular signaling (Zhang_2005). Nine ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003834607.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 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: SCV000936055.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 95 of the GJB2 protein (p.Val95Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 95 of the GJB2 protein (p.Val95Met). This variant is present in population databases (rs111033299, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 11216656, 14985372, 23668481, 27398341). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44735). 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: 16217030). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033237.4
First in ClinVar: Sep 16, 2023 Last updated: Mar 10, 2024 |
Comment:
GJB2: PM3:Very Strong, PM2, PP1
Number of individuals with the variant: 1
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Pathogenic
(Apr 29, 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: SCV002086055.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Genetic Linkage Analysis of DFNB3, DFNB9 and DFNB21 Loci in GJB2 Negative Families with Autosomal Recessive Non-syndromic Hearing Loss. | Masoudi M | Iranian journal of public health | 2016 | PMID: 27398341 |
Screening of genetic alterations related to non-syndromic hearing loss using MassARRAY iPLEX® technology. | Svidnicki MC | BMC medical genetics | 2015 | PMID: 26399936 |
GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. | Zheng J | PloS one | 2015 | PMID: 26043044 |
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 |
Spectrum and frequency of GJB2 mutations in a cohort of 264 Portuguese nonsyndromic sensorineural hearing loss patients. | Matos TD | International journal of audiology | 2013 | PMID: 23668481 |
A study of GJB2 and delGJB6-D13S1830 mutations in Brazilian non-syndromic deaf children from the Amazon region. | Castro LS | Brazilian journal of otorhinolaryngology | 2013 | PMID: 23503914 |
Universal neonatal audiological screening: experience of the University Hospital of Pisa. | Ghirri P | Italian journal of pediatrics | 2011 | PMID: 21481246 |
GJB2 mutations and genotype-phenotype correlation in 335 patients from germany with nonsyndromic sensorineural hearing loss: evidence for additional recessive mutations not detected by current methods. | Bartsch O | Audiology & neuro-otology | 2010 | PMID: 20234132 |
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 |
Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions. | Zhang Y | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 16217030 |
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 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. | Pandya A | Genetics in medicine : official journal of the American College of Medical Genetics | 2003 | PMID: 12865758 |
Functional analysis of connexin-26 mutants associated with hereditary recessive deafness. | Wang HL | Journal of neurochemistry | 2003 | PMID: 12562518 |
Exploring the clinical and epidemiological complexity of GJB2-linked deafness. | Gualandi F | American journal of medical genetics | 2002 | PMID: 12239718 |
Deafness resulting from mutations in the GJB2 (connexin 26) gene in Brazilian patients. | Oliveira CA | Clinical genetics | 2002 | PMID: 12081719 |
The M34T allele variant of connexin 26. | Cucci RA | Genetic testing | 2000 | PMID: 11216656 |
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 |
[The usefulness of the level of alpha-fetoprotein (AFP) and electrophoresis of amniotic acetylcholinesterase for the detection of selected congenital malformations]. | Lemonnier MC | Journal de gynecologie, obstetrique et biologie de la reproduction | 1990 | PMID: 1693158 |
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Text-mined citations for rs111033299 ...
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.