ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.109G>A (p.Val37Ile)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004004.6(GJB2):c.109G>A (p.Val37Ile)
Variation ID: 17023 Accession: VCV000017023.124
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189473 (GRCh38) [ NCBI UCSC ] 13: 20763612 (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 Aug 4, 2024 Jun 24, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.109G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Val37Ile missense NC_000013.11:g.20189473C>T NC_000013.10:g.20763612C>T NG_008358.1:g.8503G>A LRG_1350:g.8503G>A LRG_1350t1:c.109G>A LRG_1350p1:p.Val37Ile P29033:p.Val37Ile - Protein change
- V37I
- Other names
- NM_004004.5(GJB2):c.109G>A
- Canonical SPDI
- NC_000013.11:20189472: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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0.01538 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00354
Trans-Omics for Precision Medicine (TOPMed) 0.00451
Exome Aggregation Consortium (ExAC) 0.00659
The Genome Aggregation Database (gnomAD), exomes 0.00772
1000 Genomes Project 30x 0.01405
1000 Genomes Project 0.01538
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
562 | 628 |
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 (23) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000018550.76 | |
Pathogenic/Likely pathogenic/Pathogenic, low penetrance (13) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000080365.69 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2021 | RCV000146005.17 | |
Pathogenic (3) |
reviewed by expert panel
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Jun 24, 2019 | RCV000211759.14 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2022 | RCV000515287.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 5, 2016 | RCV001270106.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 17, 2021 | RCV001002768.16 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004396.9 | |
GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss
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Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV003458337.1 |
Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2020 | RCV002514109.10 | |
GJB2-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335045.1 |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 24, 2019)
|
reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hearing Loss Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000927014.1 First in ClinVar: Jul 22, 2019 Last updated: Jul 22, 2019 |
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)
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 gene is 7.9% for East Asian genomes in gnomAD.This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 139 homozygous affected probands, 17 affected probands with the p.Met34Thr variant in trans, 131 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans. However, because the variant is also very frequent in the general population, this criteria has been applied at the strength of Moderate. (PM3; PMID: 31160754). The p.Val37Ile variant in GJB2 has been reported to segregate with hearing loss in at least 21 family members (PP1_Strong; PMID: 31160754). Although homozygous or compound heterozygous observations have been identified in individuals with normal hearing, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance (PMID: 27308859). Furthermore, in dye transfer and electrical coupling assays, both functional studies have shown that the variant impacts protein function (PMID: 26088551, 12505163, 16300957) and knock-in mouse model demonstrated that the p.Val37Ile variant leads to the phenotype. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, and the dye transfer and coupling assays have limited validation and correlation with pathogenicity, neither was not counted as functional evidence. (PMID: 27623246). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Val37Ile in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3. (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
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000193156.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Likely pathogenic
(Oct 01, 2013)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255378.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 0-9 years
Sex: female
Testing laboratory: UCLA Clinical Genomics Center
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Likely pathogenic
(May 21, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492740.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Apr 27, 2017)
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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
|
Illumina Laboratory Services, Illumina
Accession: SCV000915626.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
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)
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 variant in a single individual with hearing loss (Abe et al. 2000). Pollak et al. (2007) found the variant was significantly overrepresented in individuals with hearing loss as compared to controls (5.2% compared to 0.43%) and suggested that this variant might cause a late onset, mild form of hearing loss with reduced penetrance when found in combination with other variants in the GJB2 gene. In an evaluation of over 1000 newborns, Wu et al. (2011) identified several homozygotes and compound heterozygotes for the p.Val37Ile variant, with both normal hearing and varying degrees of hearing loss. Expression studies have demonstrated that the p.Val37Ile variant results in a complete loss of homotypic gap junction channel activity (Snoeckx et al. 2005). The p.Val37Ile variant is reported at a frequency of 0.08586 in the Kinh in Ho Chi Minh City, Vietnam, population of the 1000 Genomes Project. This frequency is high but may be consistent with the prevalence of mild hearing loss in the population. Based on the collective evidence, the p.Val37Ile variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss, though is associated with a mild phenotype and reduced penetrance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Aug 17, 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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Eurofins Ntd Llc (ga)
Accession: SCV000700275.2
First in ClinVar: Apr 02, 2018 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 54
Sex: mixed
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138910.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
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Pathogenic
(Aug 29, 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: SCV001244779.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A homozygous missense variant was identified, NM_004004.5(GJB2):c.109G>A in exon 2 of the GJB2 gene.This substitution is predicted to create a minor amino acid change from … (more)
A homozygous missense variant was identified, NM_004004.5(GJB2):c.109G>A in exon 2 of the GJB2 gene.This substitution is predicted to create a minor amino acid change from valine to a isoleucine at position 37, NP_003995.2(GJB2):p.(Val37Ile). The valine at this position has very high conservation (100 vertebrates, UCSC).In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster) and it is not situated in a specific functional domain. This variant is present in the gnomAD population database at a frequency of 0.7% (2011 in 276450, 91 homozygotes) with an increased frequency in East Asian populations at 8.2% (1546 in 18868, 88 homozygotes). It is a variant with variable penetrance and has been reported in patients with mild to moderate hearing loss, sometimes progressive (Huang, Y. et al. (2015), Chai, Y.et al. (2014), Shen, N. et al. (2017), ClinVar). Based on current information, this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Feb 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450311.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
|
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571777.2
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment:
PS1_Very strong, PM3_Supporting, PM5_Moderate, PP3_Supporting
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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058826.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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: 31160754, PM3_M). It was co-segregated with Deafness, autosomal recessive 1A in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 16300957, 27308859, 26088551, 12505163, 31160754, 27623246) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 31160754, PS4_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 12505163, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.656, 3CNET: 0.929, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000179256,VCV000449490, PMID:15365987,17666888, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061265.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.109G>A;p.(Val37Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 17023: PMID: 31160754; 23637863; 29926981) … (more)
The c.109G>A;p.(Val37Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 17023: PMID: 31160754; 23637863; 29926981) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 26088551, 12505163, 16300957; 26088551; 31562289) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Connexin) - PM1. The p.(Val37Ile) was detected in trans with a pathogenic variant (PMID: 31160754; 26088551; 24654934; 23637863; 29926981) - PM3_very strong Pathogenic missense variant in this residue have been reported (Clinvar ID: 179256; 449490) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 31160754; 26088551; 23637863) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Jul 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579817.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PP1_STR, PM3, PP3
|
Number of individuals with the variant: 1
Sex: female
|
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Pathogenic
(Jan 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807067.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS4 strong, PM3 moderated, PP1 strong
Number of individuals with the variant: 1
Clinical Features:
Autism (present) , Asthma (present) , Allergic rhinitis (present) , Attention deficit hyperactivity disorder (present) , Hearing impairment (present) , Delayed speech and language development … (more)
Autism (present) , Asthma (present) , Allergic rhinitis (present) , Attention deficit hyperactivity disorder (present) , Hearing impairment (present) , Delayed speech and language development (present) , Small for gestational age (present) , Diabetes mellitus type 1 (present) , Astigmatism (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003924419.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
A Heterozygous Missense variant c.109G>A in Exon 2 of the GJB2 gene that results in the amino acid substitution p.Val37Ile was identified. The observed variant … (more)
A Heterozygous Missense variant c.109G>A in Exon 2 of the GJB2 gene that results in the amino acid substitution p.Val37Ile was identified. The observed variant has a minor allele frequency of 0.00772/0.00624% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 17023]. The variant has previously been reported for deafness by Shen, Jun, et al., 2019. Experimental studies have shown that this missense change disrupts the formation of homotypic junctional channels in vitro by Chen, Ying, et al., 2016. For these reasons this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935271.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
|
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Pathogenic
(Feb 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225745.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_strong, PM3, PS4
Number of individuals with the variant: 2
|
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Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603818.10
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The GJB2 c.109G>A; p.Val37Ile variant (rs72474224) is reported in the literature in multiple individuals affected with hearing loss (Baux 2017, Kecskemeti 2018, Posukh 2019, Putcha … (more)
The GJB2 c.109G>A; p.Val37Ile variant (rs72474224) is reported in the literature in multiple individuals affected with hearing loss (Baux 2017, Kecskemeti 2018, Posukh 2019, Putcha 2007, Zhou 2019). However, homozygosity for p.Val37Ile has been associated with normal hearing (Tang 2006) as well as with slight, mild or moderate hearing loss, primarily in individuals of Asian background (Bason 2002, Dahl 2006, Kim 2015, Kim 2013, Pollak 2007, Rabionet 2000). The p.Val37Ile variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 17023) and has been shown to disrupt protein function using a Xenopus oocyte-based gap junction formation assay (Bruzzone 2003) and a gap junction permeability assay in HEK293 cells (Kim 2015). This variant is found predominantly in the East Asian population with an allele frequency of 8.3% (1665/19952 alleles, including 96 homozygotes) in the Genome Aggregation Database. Additionally, other variants at this codon (c.110T>C; p.Val37Ala and c.109G>C; p.Val37Leu) have been reported in individuals with sensorineural hearing loss (Azaiez 2004, Putcha 2007). Based on available information, this variant is considered to be mildly pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 24:305-311. Bason L et al. Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss. Clin Genet. 2002 61:459-464. Baux D et al. Combined genetic approaches yield a 48% diagnostic rate in a large cohort of French hearing-impaired patients. Sci Rep. 2017 7:16783. Bruzzone R et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 533:79-88. Dahl HH et al. The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. J Med Genet. 2006 43:850-855. Kecskemeti N et al. Analysis of GJB2 mutations and the clinical manifestation in a large Hungarian cohort. Eur Arch Otorhinolaryngol. 2018 275:2441-2448. Kim J et al. Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene. Exp Mol Med. 2015 47:e169. Kim SY et al. Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity. PLoS One. 2013 8:e61592. Pollak A et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007 143A:2534-2543. Posukh OL et al. Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys). Genes (Basel). 2019 10. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 9:413-426. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 106:40-44. Tang HY et al. 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. Am J Med Genet A. 2006 140:2401-2415. Zhou Y et al. Mutation analysis of common deafness genes among 1,201 patients with non-syndromic hearing loss in Shanxi Province. Mol Genet Genomic Med. 2019 7:e537. (less)
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Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503764.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace valine with isoleucine at codon 371 of the GJB2 protein, p.(Val37Ile). The valine residue is highly conserved (100 … (more)
This sequence change is predicted to replace valine with isoleucine at codon 371 of the GJB2 protein, p.(Val37Ile). The valine residue is highly conserved (100 vertebrates, Multiz alignments), and located in the connexin domain. There is a small physicochemical difference between valine and isoleucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 4.5% (2,013/44,852 alleles, 90 homozygotes) in the East Asian population, which is higher than expected for a recessive disease. The prevalence of the variant in individuals with nonsyndromic deafness is significantly increased compared with the prevalence in controls (PMID: 31160754). The variant has been identified as compound heterozygous with a second pathogenic allele in more than a hundred individuals and homozygous in more than a hundred individuals, typically manifesting with mild to moderate hearing loss (PMID: 31160754). The variant segregates in at least 21 affected siblings over multiple families (PMID: 31160754). Additionally, in vitro functional studies of the variant demonstrate impaired function (PMID: 12505163, 16300957, 26088551). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.656). Based on the classification scheme RMH ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC, with reduced penetrance. Following criteria are met: PP1_Strong, PM3_VeryStrong, PS3_Supporting, PP3, BS1. (less)
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|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061474.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Val37Ile variant in GJB2 is a well established allele that is known to be pathogenic in the homozygous state or in the compound heterozygous … (more)
The p.Val37Ile variant in GJB2 is a well established allele that is known to be pathogenic in the homozygous state or in the compound heterozygous state with another pathogenic GJB2 variant and typically results in a mild to moderate hearing loss (Snoeckx 2005 PMID: 16380907, Huculak 2006 PMID: 17036313, Pollak 2007 PMID: 17935238). In rare cases, it may even be associated with normal hearing. Additionally, it has been reported as pathogenic in ClinVar by the ClinGen Hearing Loss Expert panel (Variation ID 17023; Shen 2019 PMID: 31160754). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss. ACMG/AMP Criteria applied: PP1_Strong, PM3_VeryStrong. (less)
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|
Pathogenic
(Apr 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500564.21
First in ClinVar: Mar 14, 2021 Last updated: Aug 04, 2024 |
Comment:
GJB2: PM3:Very Strong, PP1:Strong, PM2, PM5, PS3:Supporting
Number of individuals with the variant: 3
|
|
Pathogenic
(Oct 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Deafness, autosomal recessive 1A
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919432.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
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)
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 in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0074 in 280234 control chromosomes in the gnomAD database, including 91 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.0074 vs 0.025), allowing no conclusion about variant significance. This variant was first listed as a polymorphism by Kelley_1998 due to finding of one heterozygote of this variant in 96 control persons. However, all following studies on genotype-phenotype in patients and gene function suggest that this variant is pathogenic. In hearing loss patients with this variant, clinical severity ranges from mild to moderate. In a Chinese study (Chai_2015), the variant was strongly associated with both mild-to-moderate (p=2.01011) and severe-to-profound (p=0.001) HI, but was estimated to have a rather low penetrance (17%). Huang_2015 showed that among the 3,864 Chinese patients, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). Homozygotes of this variant or compound heterozygotes of this variant and a pathogenic variant in GJB2 were reported in patients with hearing loss in populations other than East Asian (Robionet_2000, Wilcox_2000, Snoeckx_2005). In vitro junctional conductance and biochemical permeability study on mutant Cx26 V37I showed the function of Cx26 V37I was significantly decreased (Bruzzone_2003 and Kim_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight of these have reported a classification as pathogenic (n=7) or likely pathogenic (n =1). This is consistent with the results of the "Clingen hearing loss variant curation expert panel" that has settled upon a classification for this variant as "Pathogenic" based on compelling statistical and supporting functional evidence (personal correspondence, manuscript in preparation at this time of classification) . Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Autosomal recessive nonsyndromic hearing loss 1B
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163368.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
Pathogenic
(Dec 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194147.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_004004.5(GJB2):c.109G>A(V37I) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with slowly progressive bilateral mild … (more)
NM_004004.5(GJB2):c.109G>A(V37I) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with slowly progressive bilateral mild to moderate hearing loss. Sources cited for classification include the following: PMID 12121355, 16840571, 16300957, 17935238, 10633133 and 15479191. Classification of NM_004004.5(GJB2):c.109G>A(V37I) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Aug 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
INGEBI, INGEBI / CONICET
Accession: SCV001434022.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PS4, PP1_Strong, PM3
Number of individuals with the variant: 10
Clinical Features:
Prelinegual moderate to severe bilateral hearing loss (present)
Family history: yes
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
|
|
Pathogenic
(Sep 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001438390.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Comment:
This GJB2 variant has been vetted by the ClinGen Hearing Loss Expert Panel and is predicted to be associated with autosomal recessive sensorineural hearing loss … (more)
This GJB2 variant has been vetted by the ClinGen Hearing Loss Expert Panel and is predicted to be associated with autosomal recessive sensorineural hearing loss that is typically mild to moderate and bilateral. GJB2 c.109G>A (rs72474224) reaches polymorphic frequency (>1%) within the East Asian subpopulation in a large population dataset6 (gnomAD: 1665/19952 alleles; 8.3%, 96 homozygotes), however, it was found to be significantly overrepresented in hearing loss patients compared to population controls. This variant was found to segregate with hearing loss in a large number of families. Functional studies suggest that GJB2 c.109G>A impacts connexin 26 function, however, this has not been confimed to reflect the biologic process in human cochlea. We consider this variant to be pathogenic. (less)
|
|
Pathogenic
(Aug 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hearing loss, non-syndromic
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448939.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 4
Sex: male
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810237.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
Pathogenic
(Aug 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322430.9
First in ClinVar: Oct 09, 2016 Last updated: Sep 26, 2021 |
Comment:
Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (SCV000927014.1; Landrum et al., 2016; Shen … (more)
Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (SCV000927014.1; Landrum et al., 2016; Shen et al., 2019); This variant is associated with the following publications: (PMID: 16380907, 17041943, 23873582, 27535533, 15365987, 17666888, 24077912, 31160754, 26582918, 31078570, 33095980, 32067424, 33096615, 30896630, 32386258, 31980526, 31827275, 31541171, 31914302, 30146550, 30344259, 31180159, 30733538, 31370293, 31195736, 15070423, 28489599, 29287868, 29921236, 16952406, 26119842, 26990548, 28786104, 28901477, 28012523, 25388846, 26104599, 27308839, 26896187, 27153395, 26061099, 26885124, 19043807, 27792752, 27623246, 22567861, 16840571, 26088551, 19586875, 23637863, 22574200, 24945352, 19707039, 16300957, 24212883, 22106692, 24158611, 22613756, 10830906, 12792423, 22995991, 22975760, 12505163, 24654934, 15479191, 17935238, 17036313, 25262649, 9529365, 25087612, 24645897, 23638949, 30473554, 30609409, 30693673, 30094485, 12121355, 10633133) (less)
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Pathogenic
(May 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611199.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Oct 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835039.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GJB2-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046407.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as homozygous and compound heterozygous change in patients with deafness (PMID: 31160754, 9529365, 10982180, 12121355, 16380907, 16840571, 17036313, 17041943, … (more)
This variant has been previously reported as homozygous and compound heterozygous change in patients with deafness (PMID: 31160754, 9529365, 10982180, 12121355, 16380907, 16840571, 17036313, 17041943, 17935238). Functional studies have shown a damaging effect of the variant on intercellular biochemical permeability and conductance (PMID: 12505163). This variant has been classified as Pathogenic by ClinGen Expert Panel (PMID: 31160754; ClinVar). The c.109G>A (p.Val37Ile) variant is present in the heterozygous state in the gnomAD population database in 2132/282164 individuals and homozygous state in 99 individuals, with a total allele frequency of 0.7%. Based on the available evidence, the c.109G>A (p.Val37Ile) variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004183500.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Pathogenic
(Jun 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000613504.6
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant is one of the most common variants associated with nonsyndromic hearing loss and is reported to have reduced penetrance in some families (PMID: … (more)
This variant is one of the most common variants associated with nonsyndromic hearing loss and is reported to have reduced penetrance in some families (PMID: 31160754, 30311386, 28489599). Therefore, the apparently high frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been reported in individuals with autosomal recessive nonsyndromic hearing loss and deafness. Heterozygous individuals with hearing loss have also been reported. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experimental studies demonstrate that this variant impairs homotypic junctional channel formation (PMID: 12505163, 16300957). (less)
|
|
Pathogenic
(Sep 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024259.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic, low penetrance
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000957235.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ile). This variant is present in population databases (rs72474224, gnomAD 8%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in the literature in a large meta-analysis involving several thousand cases and controls (PMID: 28489599). This variant has been reported frequently in individuals affected with mild to moderate deafness particularly among populations in eastern Asia (PMID: 23637863, 26885124, 26061099, 17036313, 16952406, 21488715). It has been shown to segregate with autosomal recessive deafness in families (PMID: 28489599, 24945352, 26088551). Although this variant is more common in the population than expected for a pathogenic variant, the penetrance of this variant is estimated to be less than 20% of other disease-causing variants in GJB2 (PMID: 17935238, 24654934). ClinVar contains an entry for this variant (Variation ID: 17023). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. Experimental studies have shown that this missense change disrupts the formation of homotypic junctional channels in vitro (PMID: 12505163). Furthermore in vivo knock-in and knock-out mouse models recapitulate the deafness phenotype observed in humans (PMID: 27623246). In summary, this variant is reported to cause sensorineural deafness. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the GJB2 gene, it has been classified as Pathogenic (low penetrance). (less)
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004812140.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS3_MOD,PM3_VSTR,PM5_STRPP1_VSTR,PP3
Clinical Features:
Hearing impairment (present)
Sex: female
|
|
Pathogenic
(Feb 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003736661.3
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.109G>A (p.V37I) alteration is located in coding exon 1 of the GJB2 gene. This alteration results from a G to A substitution at nucleotide … (more)
The c.109G>A (p.V37I) alteration is located in coding exon 1 of the GJB2 gene. This alteration results from a G to A substitution at nucleotide position 109, causing the valine (V) at amino acid position 37 to be replaced by an isoleucine (I)._x000D_ _x000D_ update for allelic disease - AD is too common Based on data from gnomAD, the A allele has an overall frequency of 0.756% (2132/282164) total alleles studied. The highest observed frequency was 8.345% (1665/19952) of East Asian alleles. This alteration has been more commonly reported in individuals of Asian ancestry (both affected and controls) (Huculak, 2006; Tang, 2006; Li, 2012). Although rare, homozygous and compound heterozygous observations have been identified in individuals with normal hearing; however presentation is typically associated with childhood onset bilateral sensorineural hearing loss (Shen, 2019; Tang, 2006). A more recent study has reported the p.V37I variant as pathogenic with variable expressivity and incomplete penetrance with progressive hearing loss over time when detected in homozygous or compound heterozygous forms (Chen, 2020). This variant has been detected as a homozygous finding in multiple families with sensorineural hearing loss (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrate an inability to induce formation of homotypic gap-junction channels, leading to a complete loss of channel activity (Bruzzone, 2003). However, large cohort studies have reported that hearing loss is typically in the mild to moderate range suggesting that the phenotypic presentation may not reflect the functional data (Snoeckx, 2005; Huculak, 2006). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051792.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Nov 01, 2007)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 1A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038832.5
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2020 |
Comment on evidence:
Bason et al. (2002) identified 3 unrelated individuals with sensorineural hearing loss (DFNB1A; 220290) who were homozygous for a val37-to-ile (V37I) missense mutation in the … (more)
Bason et al. (2002) identified 3 unrelated individuals with sensorineural hearing loss (DFNB1A; 220290) who were homozygous for a val37-to-ile (V37I) missense mutation in the GJB2 gene. One individual was of Philippine ancestry, another was from a Chinese and Cambodian background, and the third was of Chinese ancestry, raising the possibility that this mutation may be more frequent among populations in eastern Asia. V37I was reported first as a polymorphism found as a heterozygous variant in a sample from a control group (Kelley et al., 1998). Rabionet et al. (2000) identified a deaf individual who was homozygous for V37I. Dahl et al. (2006) identified a homozygous V37I mutation in 4 (8.3%) of 48 Australian children with slight or mild sensorineural hearing loss. All 4 children were of Asian background, and SNP analysis suggested a common founder effect. All 4 children showed bilateral high-frequency sensorineural hearing loss, and 3 also had low-frequency hearing loss. Two additional children who were heterozygous for V37I had mild high-frequency loss maximal at 6kHz, and mild low-frequency loss, respectively. In all, 55 children with slight or mild hearing loss were identified in a screening of 6,240 Australian school children. Huculak et al. (2006) examined the records of 40 Chinese and 40 Caucasian patients with sensorineural hearing loss who had undergone GJB2 genetic testing, and tested DNA samples from 100 Chinese and 100 Caucasian controls for V37I. The V37I allele was identified in 43.75% and 11.5% of the Chinese patient and control alleles, respectively, but was not found in either Caucasian cohort. Audiograms from 15 V37I homozygotes showed mild to moderate sensorineural hearing loss. Huculak et al. (2006) concluded that the V37I allele is common in individuals of Asian descent but rarely present in Caucasians, and that it is pathogenic but produces milder hearing loss than nonsense mutations in the GJB2 gene. Tang et al. (2006) analyzed the GJB2 gene in 610 hearing-impaired individuals and 294 controls and identified the V37I variant in 18 cases and 6 controls, including 1 control who was homozygous for the variant. The variant was found only among Asians, occurring at an allele frequency of 7.6%. Pollak et al. (2007) studied 233 Polish patients with hearing impairment and the GJB2 35delG mutation (121011.0005) on 1 allele. Analysis of 17 patients with the M34T (121011.0001)/35delG and 12 patients with the V37I/35delG genotypes, patients with other GJB2 mutations, and controls found that the M34T and V37I were significantly overrepresented among patients with hearing impairment, consistent with both variants being pathogenic. However, both mutations showed decreased penetrance of about 10% compared to mutations of undisputed pathogenicity. Also, patients with M34T/35delG and V37I/35delG had significantly later onset of hearing impairment compared to those with other genotypes. Pollak et al. (2007) suggested that the M34T and V37I mutations cause mild hearing impairment characterized by relatively late onset and progression. Shen et al. (2019) reported the results of a review of the pathogenicity of the M34T and V34I variants for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel. The panel found that the M34T and V37I variants were statistically overrepresented in hearing loss patients compared with population controls. Individuals homozygous or compound heterozygous for either of these variants had mild to moderate hearing loss. The panel concluded that both variants are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance. (less)
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453355.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808559.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744210.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001975630.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001951961.2 First in ClinVar: Oct 02, 2021 Last updated: Dec 25, 2021 |
|
|
Pathogenic
(Jan 23, 2015)
|
no assertion criteria provided
Method: research
|
Deafness, autosomal recessive 1A
Affected status: no
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238418.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
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)
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) identified in this patient is a missense variant reported to be a common pathogenic variant in individuals with Asian ancestry and is associated with mild to moderate, sometimes progressive hearing impairment in individuals with various ages. (Gallant et al. 2013, PMID: 23873582; Huculak et al. 2006, PMID: 17036313; Bruzzone et al. 2003, PMID: 12505163; Li et al. 2012, PMID: 22574200) (less)
|
|
Likely pathogenic
(Feb 26, 2019)
|
no assertion criteria provided
Method: case-control
|
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: SCV000902313.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 26
Clinical Features:
hearing loss (present)
Family history: yes
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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: SCV000041039.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Uncertain significance
(May 09, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
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Deafness, autosomal recessive 1A
Affected status: no, yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599730.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Number of individuals with the variant: 36
Observation 2:
Number of individuals with the variant: 5
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Likely benign
(-)
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Flagged submission
flagged submission
Method: case-control
Reason: Unnecessary conflicting claim for distinct condition when other classifications are more relevant
Source: ClinGen
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: no
Allele origin:
maternal
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000992412.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
Number of individuals with the variant: 2
Clinical Features:
hearing loss (present) , Postnatal growth retardation (present) , Ocular hypertelorism (present) , low-set ears (present) , downslanting palpebral fissures (present)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
---|---|---|---|---|
GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss. | Adam MP | - | 2023 | PMID: 20301449 |
Biallelic p.V37I variant in GJB2 is associated with increasing incidence of hearing loss with age. | Chen Y | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35016843 |
Hearing consequences in Gjb2 knock-in mice: implications for human p.V37I mutation. | Lin X | Aging | 2019 | PMID: 31562289 |
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 |
Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. | Oza AM | Human mutation | 2018 | PMID: 30311386 |
GJB3/GJB6 screening in GJB2 carriers with idiopathic hearing loss: Is it necessary? | Chen K | Journal of clinical laboratory analysis | 2018 | PMID: 29926981 |
Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis. | Shen N | Oncotarget | 2017 | PMID: 28489599 |
Newborn genetic screening for hearing impairment: a population-based longitudinal study. | Wu CC | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27308839 |
Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2. | Chen Y | Scientific reports | 2016 | PMID: 27623246 |
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 |
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 |
Correlation analysis of phenotype and genotype of GJB2 in patients with non-syndromic hearing loss in China. | Dai ZY | Gene | 2015 | PMID: 26095810 |
Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population. | Kim SY | PloS one | 2015 | PMID: 26061264 |
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 |
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 |
Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. | Abe K | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24762805 |
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 |
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 |
Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss. | Riahi Z | Gene | 2013 | PMID: 23680645 |
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 |
The p.V37I exclusive genotype of GJB2: a genetic risk-indicator of postnatal permanent childhood hearing impairment. | Li L | PloS one | 2012 | PMID: 22574200 |
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 |
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 |
The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. | Makita N | The Journal of clinical investigation | 2008 | PMID: 18451998 |
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 |
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 |
GJB2: the spectrum of deafness-causing allele variants and their phenotype. | Azaiez H | Human mutation | 2004 | PMID: 15365987 |
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 |
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 |
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 |
Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. | Wei J | Circulation | 1999 | PMID: 10377081 |
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 | - | - | - | - |
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Text-mined citations for rs72474224 ...
HelpRecord last updated Sep 01, 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.