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NM_004004.6(GJB2):c.109G>A (p.Val37Ile)

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Interpretation:
Pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
19 (Most recent: Jul 18, 2019)
Last evaluated:
Jun 24, 2019
Accession:
VCV000017023.10
Variation ID:
17023
Description:
single nucleotide variant
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NM_004004.6(GJB2):c.109G>A (p.Val37Ile)

Allele ID
32062
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
13q12.11
Genomic location
13: 20189473 (GRCh38) GRCh38 UCSC
13: 20763612 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000013.10:g.20763612C>T
NC_000013.11:g.20189473C>T
NM_004004.6:c.109G>A NP_003995.2:p.Val37Ile missense
... more HGVS
Protein change
V37I
Other names
NM_004004.5(GJB2):c.109G>A
Functional consequence
-
Global minor allele frequency (GMAF)
0.01538 (T)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00605
The Genome Aggregation Database (gnomAD), exomes 0.00772
1000 Genomes Project 0.01538
The Genome Aggregation Database (gnomAD) 0.00624
Exome Aggregation Consortium (ExAC) 0.00659
Links
ClinGen: CA172210
UniProtKB: P29033#VAR_002139
OMIM: 121011.0023
dbSNP: rs72474224
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 1 reviewed by expert panel Jun 24, 2019 RCV000211759.4
Pathogenic 5 criteria provided, multiple submitters, no conflicts Jan 6, 2019 RCV000080365.10
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts May 21, 2014 RCV000146005.2
Likely pathogenic 1 criteria provided, single submitter May 18, 2017 RCV000515287.1
Pathogenic 1 criteria provided, single submitter Jan 24, 2011 RCV000844700.1
Conflicting interpretations of pathogenicity 9 criteria provided, conflicting interpretations Oct 15, 2018 RCV000018550.39
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
GJB2 Dosage sensitivity unlikely No evidence available GRCh38
GRCh37
296 345

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Jun 24, 2019)
reviewed by expert panel
Method: curation
Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Allele origin: germline
ClinGen Hearing Loss Variant Curation Expert Panel,
FDA Recognized Database
Accession: SCV000927014.1
Submitted: (Jul 18, 2019)
Evidence details
Publications
PubMed (1)
Other databases
https://erepo.clinicalgenome.o...
Comment:
The filtering allele frequency (the lower threshold of the 95% CI of 143/1558, including 8 homozygous observations) of the c.109G>A (p.Val37Ile) variant in the GJB2 ... (more)
Pathogenic
(Feb 08, 2013)
criteria provided, single submitter
Method: clinical testing
Hearing impairment
(Autosomal recessive inheritance)
Allele origin: germline
Genetic Services Laboratory, University of Chicago
Accession: SCV000193156.1
Submitted: (Sep 11, 2014)
Evidence details
Uncertain significance
(May 09, 2017)
criteria provided, single submitter
Method: clinical testing
Deafness, autosomal recessive 1A
Allele origin: germline
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia
Accession: SCV000599730.1
Submitted: (May 17, 2017)
Evidence details
Likely pathogenic
(May 18, 2017)
criteria provided, single submitter
Method: clinical testing
Mutilating keratoderma
Keratitis-ichthyosis-deafness syndrome, autosomal dominant
Keratoderma palmoplantar deafness
Knuckle pads, deafness AND leukonychia syndrome
Deafness, autosomal recessive 1A
Deafness, X-linked 2
Deafness, autosomal dominant 3a
Hystrix-like ichthyosis with deafness
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000611199.1
Submitted: (May 23, 2017)
Evidence details
Pathogenic
(Feb 26, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV000613504.2
Submitted: (Aug 31, 2018)
Evidence details
Publications
PubMed (48)
Pathogenic
(May 26, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603818.2
Submitted: (Oct 10, 2018)
Evidence details
Pathogenic
(Oct 10, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000322430.8
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The V37I variant in the GJB2 gene has been reported frequently in association with autosomal recessive nonsyndromic sensorineural hearing loss (NSHL) of mild severity compared ... (more)
Pathogenic
(Oct 15, 2018)
criteria provided, single submitter
Method: clinical testing
Deafness, autosomal recessive 1A
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000919432.1
Submitted: (Apr 24, 2019)
Evidence details
Publications
PubMed (18)
Comment:
Variant summary: GJB2 c.109G>A (p.Val37Ile) results in a conservative amino acid change located in the Connexin, N-terminal of the encoded protein sequence. Three of five ... (more)
Pathogenic
(Jan 06, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV000957235.1
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (11)
Comment:
This sequence change replaces valine with isoleucine at codon 37 of the GJB2 protein (p.Val37Ile). The valine residue is highly conserved and there is a ... (more)
Pathogenic
(Jan 24, 2011)
criteria provided, single submitter
Method: clinical testing
Rare genetic deafness
(Autosomal recessive inheritance)
Allele origin: germline
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
Accession: SCV000061474.5
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (3)
Comment:
The p.Val37Ile variant in GJB2 is known to be pathogenic and, in homozygosity or when combined with another GJB2 variant, typically results in a mild ... (more)
Likely pathogenic
(Oct 01, 2013)
criteria provided, single submitter
Method: clinical testing
Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Allele origin: germline
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255378.2
Submitted: (May 14, 2015)
Evidence details
Likely pathogenic
(May 21, 2014)
criteria provided, single submitter
Method: clinical testing
Hearing impairment
Allele origin: unknown
Centre for Mendelian Genomics,University Medical Centre Ljubljana
Accession: SCV000492740.1
Submitted: (Nov 12, 2016)
Evidence details
Pathogenic
(Oct 28, 2015)
criteria provided, single submitter
Method: clinical testing
Deafness, autosomal recessive 1A
Allele origin: unknown
Counsyl
Accession: SCV000678021.1
Submitted: (Jun 22, 2017)
Evidence details
Publications
PubMed (9)
Comment:
V37I is associated with a variable presentation, ranging from clinically asymptomatic to severe hearing loss.
Pathogenic
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Deafness, autosomal recessive 1A
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000915626.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (4)
Comment:
The GJB2 c.109G>A (p.Val37Ile) missense variant is widely reported in the literature. The variant was first identified in a compound heterozygous state with a second ... (more)
Pathogenic
(Aug 17, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000700275.2
Submitted: (Jun 30, 2017)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
Pathogenic
(Nov 01, 2007)
no assertion criteria provided
Method: literature only
DEAFNESS, AUTOSOMAL RECESSIVE 1A
Allele origin: germline
OMIM
Accession: SCV000038832.4
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (7)
pathologic
(Jul 14, 2011)
no assertion criteria provided
Method: curation
DFNB 1 Nonsyndromic Hearing Loss and Deafness
Allele origin: not provided
GeneReviews
Accession: SCV000041039.2
Submitted: (Dec 02, 2013)
Evidence details
Comment:
Converted during submission to Pathogenic.
Pathogenic
(Jan 23, 2015)
no assertion criteria provided
Method: research
Deafness, autosomal recessive 1A
Allele origin: germline
Division of Human Genetics,Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238418.1
Submitted: (Jun 26, 2015)
Evidence details
Publications
PubMed (2)
Comment:
This patient is a carrier of a heterozygous pathogenic variant in the GJB2 gene associated with autosomal recessive deafness 1A. The GJB2 variant (c.109G>A; p.V37I) ... (more)
Likely pathogenic
(Feb 26, 2019)
no assertion criteria provided
Method: case-control
Deafness, autosomal recessive 1A
Allele origin: inherited
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902313.1
Submitted: (Apr 29, 2019)
Evidence details

Citations for this variant

Title Author Journal Year Link
Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Shen J Genetics in medicine : official journal of the American College of Medical Genetics 2019 PMID: 31160754
Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis. Shen N Oncotarget 2017 PMID: 28489599
The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. Mikstiene V BMC genetics 2016 PMID: 26896187
Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation. Yuan Y BMC genetics 2016 PMID: 26832775
Nonsyndromic Hearing Loss and Deafness, DFNB1 Smith RJH - 2016 PMID: 20301449
Prevalence of p.V37I variant of GJB2 among Chinese infants with mild or moderate hearing loss. Huang Y International journal of clinical and experimental medicine 2015 PMID: 26885124
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
Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene. Kim J Experimental & molecular medicine 2015 PMID: 26088551
Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population. Kim SY PloS one 2015 PMID: 26061264
The Relationship between the p.V37I Mutation in GJB2 and Hearing Phenotypes in Chinese Individuals. Huang S PloS one 2015 PMID: 26061099
The homozygous p.V37I variant of GJB2 is associated with diverse hearing phenotypes. Chai Y Clinical genetics 2015 PMID: 24654934
Clinical exome sequencing for genetic identification of rare Mendelian disorders. Lee H JAMA 2014 PMID: 25326637
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Shearer AE American journal of human genetics 2014 PMID: 25262649
Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans. Pang X PloS one 2014 PMID: 24945352
Newborn dried blood-spot screening of the p.V37I variant of GJB2 by high-resolution melting analysis. Chen Y International journal of pediatric otorhinolaryngology 2014 PMID: 24814571
Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non‑syndromic hearing loss. Jiang H Molecular medicine reports 2014 PMID: 24737404
Update of the spectrum of GJB2 mutations in 107 patients with nonsyndromic hearing loss in the Fujian population of China. Chen T Annals of human genetics 2014 PMID: 24645897
Spectrum and frequency of GJB2 mutations causing deafness in the northwest of Iran. Bonyadi MJ International journal of pediatric otorhinolaryngology 2014 PMID: 24529908
Homozygosity for the V37I GJB2 mutation in fifteen probands with mild to moderate sensorineural hearing impairment: further confirmation of pathogenicity and haplotype analysis in Asian populations. Gallant E American journal of medical genetics. Part A 2013 PMID: 23873582
Compound heterozygosity for dominant and recessive GJB2 mutations in a Tunisian family and association with successful cochlear implant outcome. Riahi Z International journal of pediatric otorhinolaryngology 2013 PMID: 23856378
Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss. Riahi Z Gene 2013 PMID: 23680645
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
An informatics approach to analyzing the incidentalome. Berg JS Genetics in medicine : official journal of the American College of Medical Genetics 2013 PMID: 22995991
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Lazarin GA Genetics in medicine : official journal of the American College of Medical Genetics 2013 PMID: 22975760
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
Mutation detection in GJB2 gene among Malays with non-syndromic hearing loss. Zainal SA International journal of pediatric otorhinolaryngology 2012 PMID: 22613756
The p.V37I exclusive genotype of GJB2: a genetic risk-indicator of postnatal permanent childhood hearing impairment. Li L PloS one 2012 PMID: 22574200
Molecular screening of patients with nonsyndromic hearing loss from Nanjing city of China. Lu Y Journal of biomedical research 2011 PMID: 23554706
The association between GJB2 mutation and GJB6 gene in non syndromic hearing loss school children. Asma A The Medical journal of Malaysia 2011 PMID: 22106692
Determination of the carrier frequencies of selected GJB2 mutations in the Korean population. Kim SY International journal of audiology 2011 PMID: 21815880
Newborn genetic screening for hearing impairment: a preliminary study at a tertiary center. Wu CC PloS one 2011 PMID: 21811586
Phenotype-genotype correlation in 295 Chinese deaf subjects with biallelic causative mutations in the GJB2 gene. Zhao FF Genetic testing and molecular biomarkers 2011 PMID: 21488715
High prevalence of the connexin 26 (GJB2) mutation in Chinese cochlear implant recipients. Chen D ORL; journal for oto-rhino-laryngology and its related specialties 2009 PMID: 19707039
[Mutations of Cx26 gene in patients with NSHL and intracellular distribution of two mutants]. Li JZ Yi chuan = Hereditas 2009 PMID: 19586875
Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. Han SH Journal of human genetics 2008 PMID: 19043807
M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Pollak A American journal of medical genetics. Part A 2007 PMID: 17935238
The fate of 12 recessive mutations in a single village. Zlotogora J Annals of human genetics 2007 PMID: 17331080
DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Tang HY American journal of medical genetics. Part A 2006 PMID: 17041943
V37I connexin 26 allele in patients with sensorineural hearing loss: evidence of its pathogenicity. Huculak C American journal of medical genetics. Part A 2006 PMID: 17036313
Two patients with the V37I/235delC genotype: are radiographic cochlear anomalies part of the phenotype? Schrijver I International journal of pediatric otorhinolaryngology 2006 PMID: 16952406
The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. Dahl HH Journal of medical genetics 2006 PMID: 16840571
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
Congenital deafness: high prevalence of a V37I mutation in the GJB2 gene among deaf school children in Alor Setar. Ruszymah BH The Medical journal of Malaysia 2005 PMID: 16379178
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
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
High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals. Wattanasirichaigoon D Clinical genetics 2004 PMID: 15479191
Prevalence of the GJB2 mutations and the del(GJB6-D13S1830) mutation in Brazilian patients with deafness. Belintani Piatto V Hearing research 2004 PMID: 15464305
Molecular epidemiology of DFNB1 deafness in France. Roux AF BMC medical genetics 2004 PMID: 15070423
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 NM Human mutation 2004 PMID: 14722929
High frequency of GJB2 mutation W24X among Slovak Romany (Gypsy) patients with non-syndromic hearing loss (NSHL). Minárik G General physiology and biophysics 2003 PMID: 15113126
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
A novel dominant missense mutation--D179N--in the GJB2 gene (Connexin 26) associated with non-syndromic hearing loss. Primignani P Clinical genetics 2003 PMID: 12786758
GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Ohtsuka A Human genetics 2003 PMID: 12560944
Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. Bruzzone R FEBS letters 2003 PMID: 12505163
Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss. Bason L Clinical genetics 2002 PMID: 12121355
Connexin 26 gene (GJB2) mutation modulates the severity of hearing loss associated with the 1555A-->G mitochondrial mutation. Abe S American journal of medical genetics 2001 PMID: 11746015
Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Rabionet R Human genetics 2000 PMID: 10982180
High frequency hearing loss correlated with mutations in the GJB2 gene. Wilcox SA Human genetics 2000 PMID: 10830906
Prevalent connexin 26 gene (GJB2) mutations in Japanese. Abe S Journal of medical genetics 2000 PMID: 10633133
Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. Kudo T American journal of medical genetics 2000 PMID: 10607953
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/69193dd4-e172-4874-984a-28596f644cae - - - -

Record last updated Nov 10, 2019