ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.439G>A (p.Glu147Lys)
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.439G>A (p.Glu147Lys)
Variation ID: 371709 Accession: VCV000371709.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189143 (GRCh38) [ NCBI UCSC ] 13: 20763282 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 Apr 15, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.439G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Glu147Lys missense NC_000013.11:g.20189143C>T NC_000013.10:g.20763282C>T NG_008358.1:g.8833G>A LRG_1350:g.8833G>A LRG_1350t1:c.439G>A LRG_1350p1:p.Glu147Lys - Protein change
- E147K
- Other names
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- Canonical SPDI
- NC_000013.11:20189142:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2017 | RCV000409580.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2016 | RCV000411084.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 22, 2023 | RCV000488996.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2016 | RCV000506862.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2018 | RCV000825565.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257565.3 |
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 15, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603819.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Sep 21, 2018)
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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: SCV000966892.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Glu147Lys variant in GJB2 has been reported in 8 individuals with hearing loss, including 3 homozygotes and 5 individuals who were compound heterozygous f … (more)
The p.Glu147Lys variant in GJB2 has been reported in 8 individuals with hearing loss, including 3 homozygotes and 5 individuals who were compound heterozygous f or a second pathogenic variant (Cryns 2004, de Oliveira 2007, Dodson 2011, Frei 2004, Gravina 2010, Lin 2011, Snoeckx 2005, Zheng 2015). In addition, the varian t segregated in the homozygous state in two affected siblings in one family (Fre i 2004). This variant is present in 3/245794 total chromosomes by gnomAD (http:/ /gnomad.broadinstitute.org), which is low enough to be consistent with a recessi ve carrier frequency. Computational prediction tools and conservation analysis s uggest an impact to the protein. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP1_Moderate, PP3. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 04, 2017)
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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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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244785.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A heterozygous missense variant was identified, NM_004004.5(GJB2):c.439G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from a glutamic … (more)
A heterozygous missense variant was identified, NM_004004.5(GJB2):c.439G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from a glutamic acid to a lysine at position 147, NP_003995.2(GJB2):p.(Glu147Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC) and in silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster).This variant is present in the gnomAD population database at a frequency of 0.001% and it has been previously reported in patients with autosomal recessive deafness (ClinVar, Frei, K. et al. (2004) and Cryns, K. et al. (2004)).It is situated in the third transmembrane domain, which has been shown to be essential for protein function (Frei K. et al. (2004). Based on current information and in association with the NM_004004.5(GJB2):c.35delG deletion variant, this variant has been classified as PATHOGENIC.The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness. (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: SCV001434019.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.439G>A, p.(Glu147Lys) was observed only once in South Asian, Latino and European non-Finnish … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.439G>A, p.(Glu147Lys) was observed only once in South Asian, Latino and European non-Finnish populations from Genome Aggregation Database (http://gnomad.broadinstitute.org), meeting PM2 criteria. This was detected in trans with at least 4 different pathogenic variants applying to PM3_VeryStrong rule (PMID: 14676473, 21131880, 14985372, 21465647, 26043044). Besides, it segregated in three affected siblings with congenital moderate-profound hearing loss meeting PP1_Moderate criteria (PMID:14676473). Computational evidence predicted a damage impact of the mutation to the protein (REVEL score: 0,94; PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PM3_VeryStrong, PP1_Moderate and PP3. (less)
Number of individuals with the variant: 1
Clinical Features:
Postlingual bilateral hearing loss (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Likely pathogenic
(Feb 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487518.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Feb 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487519.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jul 18, 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: SCV000576949.7
First in ClinVar: May 22, 2017 Last updated: Jul 29, 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: 15253766, … (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: 15253766, 26188157, 25149764, 29921236, 30168495, 29542069, 14676473, 19371219, 14985372, 16380907, 16125251, 17567887, 20022641, 21465647, 26346709, 25388846, 26043044, 30094485, 31215297, 30989077, 30344259, 21131880, 31160754, 30275481, 32645618, 33096615, 31589614, 29871260, 31541171, 31827275) (less)
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Pathogenic
(Oct 22, 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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Invitae
Accession: SCV002228260.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the GJB2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the GJB2 protein (p.Glu147Lys). This variant is present in population databases (rs767178508, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 14676473, 21465647, 30168495, 30344259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 371709). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2019)
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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: SCV001245648.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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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: SCV000902312.1
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: SCV001463367.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(May 11, 2022)
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no assertion criteria provided
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV002754542.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 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 Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia. | Plevova P | Medicina (Kaunas, Lithuania) | 2018 | PMID: 30344259 |
Spectrum of GJB2 gene variants in Indian children with non-syndromic hearing loss. | Singh PK | The Indian journal of medical research | 2018 | PMID: 30168495 |
GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. | Zheng J | PloS one | 2015 | PMID: 26043044 |
Vestibular dysfunction in DFNB1 deafness. | Dodson KM | American journal of medical genetics. Part A | 2011 | PMID: 21465647 |
Comprehensive diagnostic battery for evaluating sensorineural hearing loss in children. | Lin JW | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2011 | PMID: 21131880 |
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 |
Molecular genetics study of deafness in Brazil: 8-year experience. | de Oliveira CA | American journal of medical genetics. Part A | 2007 | PMID: 17567887 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
A novel connexin 26 mutation associated with autosomal recessive sensorineural deafness. | Frei K | Audiology & neuro-otology | 2004 | PMID: 14676473 |
Text-mined citations for rs767178508 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.