ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.167del (p.Leu56fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004004.6(GJB2):c.167del (p.Leu56fs)
Variation ID: 17010 Accession: VCV000017010.71
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189415 (GRCh38) [ NCBI UCSC ] 13: 20763554 (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 May 1, 2024 Sep 19, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.167del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Leu56fs frameshift NM_004004.6:c.167delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000013.11:g.20189415del NC_000013.10:g.20763554del NG_008358.1:g.8561del LRG_1350:g.8561del LRG_1350t1:c.167del LRG_1350p1:p.Leu56fs - Protein change
- L56fs
- Other names
- NM_004004.5(GJB2):c.167delT(p.Leu56Argfs)
- NM_004004.5(GJB2):c.167delT
- Canonical SPDI
- NC_000013.11:20189414:A:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00058
Trans-Omics for Precision Medicine (TOPMed) 0.00062
Exome Aggregation Consortium (ExAC) 0.00068
The Genome Aggregation Database (gnomAD), exomes 0.00089
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 |
556 | 619 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 18, 2015 | RCV000409300.11 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Apr 28, 2023 | RCV000018534.54 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 25, 2016 | RCV000477920.9 | |
Pathogenic (1) |
no assertion criteria provided
|
May 22, 2013 | RCV000678869.9 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004395.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000146010.13 | |
Pathogenic (2) |
reviewed by expert panel
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Sep 19, 2018 | RCV000211757.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2021 | RCV002227040.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 2, 2020 | RCV002470713.8 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000255988.45 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV000291910.16 | |
Pathogenic (1) |
criteria provided, single submitter
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May 16, 2018 | RCV000346888.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2022 | RCV002504803.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 11, 2020 | RCV002513103.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2011 | RCV000844699.12 | |
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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
(Sep 19, 2018)
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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
Accession: SCV000840535.4
First in ClinVar: May 03, 2018 Last updated: Dec 11, 2022 |
Comment:
The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; … (more)
The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive nonsyndromic hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 24529908, 26096904, 24158611, 9285800, 17666888). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, BA1. (less)
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193161.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(May 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: yes, no
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599734.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Number of individuals with the variant: 17
Observation 2:
Number of individuals with the variant: 5
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Pathogenic
(Jul 30, 2015)
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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: SCV000330926.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 11
Sex: mixed
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Pathogenic
(May 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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GJB2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000383032.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The GJB2 c.167delT (p.Leu56ArgfsTer26) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu56ArgfsTer26 variant is a … (more)
The GJB2 c.167delT (p.Leu56ArgfsTer26) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu56ArgfsTer26 variant is a well-known variant that is common in the Ashkenazi Jewish population, where the carrier rate is as high as 7.5% (Lerer et al. 2000). Across a selection of the available literature, the p.Leu56ArgfsTer26 variant has been identified in a total of 34 patients with autosomal recessive nonsyndromic hearing loss, including in 16 in a homozygous state, in 15 in a compound heterozygous state, and in three in a heterozygous state (Zelante et al. 1997; Morell et al. 1998; Lerer et al. 2000; Batissoco et al. 2009; Bonyadi et al. 2014; Amorini et al. 2015). The p.Leu56ArgfsTer26 variant was shown to segregate with disease in at least one family. Patients with this variant show a spectrum of phenotypic manifestation from mild to profound hearing loss, even among affected family members (Morell et al. 1998). Control data is unavailable for this variant, which is reported at a frequency of 0.00145 in the European-American population of the Exome Sequencing Project (Morell et al. 1998; Lerer et al. 2000). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu56ArgfsTer26 variant is classified as pathogenic for GJB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 08, 2011)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061479.5
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Comment:
The c.167delT variant in GJB2 is known to be pathogenic with many supporting pub lications. PVS1, PM3_VeryStrong.
Number of individuals with the variant: 39
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Autosomal recessive nonsyndromic hearing loss 1B
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163367.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Oct 18, 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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Myriad Genetics, Inc.
Accession: SCV001193832.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_004004.5(GJB2):c.167delT(L56Rfs*26) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Please note that L56Rfs*26 is associated with a variable … (more)
NM_004004.5(GJB2):c.167delT(L56Rfs*26) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Please note that L56Rfs*26 is associated with a variable presentation, ranging from mild to profound hearing loss. Sources cited for classification include the following: PMID 24158611, 10049954, 16380907, 10596881, 11556849, 11074495, and 10982182. Classification of NM_004004.5(GJB2):c.167delT(L56Rfs*26) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Aug 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001434023.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS
Number of individuals with the variant: 13
Clinical Features:
Prelinegual moderate to profound bilateral hearing loss (present)
Family history: no
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Pathogenic
(Sep 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321727.7
First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019 |
Comment:
Most individuals heterozygous for the c.167delT variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination … (more)
Most individuals heterozygous for the c.167delT variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination (Morell et al., 1998); Frameshift variant predicted to result in protein truncation, as the last 171 amino acids are lost and replaced with 25 incorrect amino acids (Stenson et al., 2014); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840535.3; Oza et al., 2018); Observed in 218/276720 (0.08%) alleles from individuals in large population cohorts, including 3 homozygous individuals (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27153395, 28702509, 22785241, 17666888, 24158611, 31160754, 25262649, 21465647, 22975760, 20739944, 11668644, 9819448, 26896187, 9285800, 26990548, 16380907, 15967879, 10982182, 23891399, 10903123, 20301449, 26096904, 24529908, 19125024, 15547683, 26236732, 11935342, 11386851, 29542069, 29984802, 27018795, 29431110, 11074495, 31370293, 31827275, 31980526, 32747562, 33096615, 31589614, 32067424) (less)
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Pathogenic
(Jan 03, 2022)
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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:
germline
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3billion
Accession: SCV002058402.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated … (more)
Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000017010, PMID:9285800). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000804, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 24158611, 9285800, 24529908, 26096904, 17666888, PM3_VS). 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
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506439.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
ACMG categories: PVS1,PM2,PP5
Number of individuals with the variant: 1
Clinical Features:
Conductive hearing impairment (present) , Sensorineural hearing loss disorder (present) , Global developmental delay (present) , Delayed speech and language development (present) , Aggressive behavior … (more)
Conductive hearing impairment (present) , Sensorineural hearing loss disorder (present) , Global developmental delay (present) , Delayed speech and language development (present) , Aggressive behavior (present) (less)
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mutilating keratoderma
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516477.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Dec 18, 2015)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487400.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
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Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics Inc
Accession: SCV000613506.4
First in ClinVar: Oct 09, 2016 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. This variant is the most common pathogenic variant among the Ashkenazi Jewish … (more)
This variant is expected to result in the loss of a functional protein. This variant is the most common pathogenic variant among the Ashkenazi Jewish population (PMID: 9819448), and therefore, the observed frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with nonsyndromic hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. (less)
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Pathogenic
(Apr 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003927250.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
|
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024265.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000940600.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu56Argfs*26) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Leu56Argfs*26) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 171 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338942, gnomAD 1.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 9819448, 10982182, 11935342, 15967879, 16380907, 21465647, 22695344, 24158611). ClinVar contains an entry for this variant (Variation ID: 17010). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160051.4
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The GJB2 c.167delT; p.Leu56fs variant (rs80338942) creates a frameshift and is predicted to result in a truncated protein or absent transcript. Homozygous and compound heterozygous … (more)
The GJB2 c.167delT; p.Leu56fs variant (rs80338942) creates a frameshift and is predicted to result in a truncated protein or absent transcript. Homozygous and compound heterozygous c.167delT variants have been reported in a number of patients with hearing loss (Kenna 2010, Snoeckx 2005). This variant is reported to ClinVar (Variation ID: 17010), and observed in the general population databases with an overall allele frequency of 0.08 percent (218/276720 alleles), including 3 homozygotes (Genome Aggregation Database). Importantly, this variant has been reported at a carrier frequency of 2.4-7.5 percent in Ashkenazi Jewish individuals (Bors 2004, Lerer 2000, Morell 1998, Sobe 1999). Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.167delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/17010/ Bors A. et al. Frequencies of two common mutations (c.35delG and c.167delT) of the connexin 26 gene in different populations of Hungary. Int J Mol Med. 2004; 14(6):1105-1108. Gualandi F et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet. 2002 Sep 15;112(1):38-45. Kenna MA et al. Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss. Arch Otolaryngol Head Neck Surg 2010; 136(1):81-87. Lerer I et al. Contribution of connexin 26 mutations in non-syndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. Am. J. Med. Genet. 2000; 95:53-56. Morell RJ et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 1998; 339(21):1500-1505. Snoeckx RL et al. GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet 2005; 77:945-957. Sobe T et al. High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. Am J Med Genet. 1999; 86:499-500. (less)
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Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334475.19
First in ClinVar: Jun 08, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Feb 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003743260.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.167delT (p.L56Rfs*26) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, … (more)
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.167delT (p.L56Rfs*26) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, results from a deletion of one nucleotide at position 167, causing a translational frameshift with a predicted alternate stop codon after 26 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of GJB2, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last three-quarters of the protein. The alteration has been observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GJB2 c.167delT alteration was observed in 0.08% (227/282466) of total alleles studied, with a frequency of 1.6% (168/10326) in the Ashkenazi Jewish subpopulation, including 3 homozygotes. The alteration has been observed in affected individuals: _x000D_ _x000D_ That alteration has been observed in conjunction with a second disease-causing allele in multiple individuals with non-syndromic hearing loss (Zelante, 1997; Morell, 1998; Dzhemileva, 2010; Mikstiene, 2016). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Aug 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698231.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Comment:
Variant summary: The c.167delT variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known … (more)
Variant summary: The c.167delT variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.269dupT, c.313_326del, c.647_650delGATA, etc.). This variant was found in 84/123144 control chromosomes (3 homozygotes) at a frequency of 0.0006821, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is a well-known common pathogenic variant predominantly found in Ashkenazi Jewish population. In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic. (less)
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Pathogenic
(Jul 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001244780.2
First in ClinVar: May 04, 2020 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive non syndromic hearing loss. However dominant negative is a likely mechanism for missense variants (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants most likely to result in lost protein function are more commonly reported for recessive disease, while missense are more commonly reported for dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Two missense variants are most commonly reported with incomplete penetrance (PMID:31160754). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD v2 >=0.01 and <0.03 for a recessive condition (221 heterozygotes, 3 homozygotes). (I) 0701 - Other truncating variants downstream of the one identified in this case have very strong previous evidence for pathogenicity. Patients with these variants are generally reported with non syndromic autosomal recessive hearing loss (ClinVar, PMID: 26096904). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been reported in patients with autosomal recessive non syndromic hearing loss (ClinVar, PMID: 26096904) (SP) 1205 - This variant has been shown to be maternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mutilating keratoderma
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Palmoplantar keratoderma-deafness syndrome Knuckle pads, deafness AND leukonychia syndrome Autosomal recessive nonsyndromic hearing loss 1A X-linked mixed hearing loss with perilymphatic gusher Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804997.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 19, 1998)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 1A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038816.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2014 |
Comment on evidence:
Morell et al. (1998) found homozygosity for 167delT and compound heterozygosity for this mutation of GJB2 and the 30delG mutation (121011.0005) in Ashkenazi Jewish families … (more)
Morell et al. (1998) found homozygosity for 167delT and compound heterozygosity for this mutation of GJB2 and the 30delG mutation (121011.0005) in Ashkenazi Jewish families with nonsyndromic recessive deafness (220290). In the Ashkenazi Jewish population, the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03%. The frequency of carriers of the 30delG and the 167delT mutation (totaling 4.76%) predicted a prevalence of 1 deaf person among 1,765 persons, which may account for most cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggested that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggested that this site is a hotspot for recurrent mutations. (less)
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Pathogenic
(May 22, 2013)
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no assertion criteria provided
Method: clinical testing
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Hearing loss
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805062.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453351.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Jan 25, 2016)
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no assertion criteria provided
Method: research
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Knuckle pads, deafness AND leukonychia syndrome
Ichthyosis, hystrix-like, with hearing loss Palmoplantar keratoderma-deafness syndrome Autosomal dominant nonsyndromic hearing loss 3A Mutilating keratoderma Autosomal recessive nonsyndromic hearing loss 1A Autosomal dominant keratitis-ichthyosis-hearing loss syndrome
Affected status: unknown
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536799.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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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: SCV000041040.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss. | Adam MP | - | 2023 | PMID: 20301449 |
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 |
SeqTailor: a user-friendly webserver for the extraction of DNA or protein sequences from next-generation sequencing data. | Zhang P | Nucleic acids research | 2019 | PMID: 31045209 |
Induction of cell death and gain-of-function properties of connexin26 mutants predict severity of skin disorders and hearing loss. | Press ER | The Journal of biological chemistry | 2017 | PMID: 28428247 |
Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic). | Barashkov NA | PloS one | 2016 | PMID: 27224056 |
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 |
Cochlear Implant Outcomes and Genetic Mutations in Children with Ear and Brain Anomalies. | Busi M | BioMed research international | 2015 | PMID: 26236732 |
Prevalence of Deafness-Associated Connexin-26 (GJB2) and Connexin-30 (GJB6) Pathogenic Alleles in a Large Patient Cohort from Eastern Sicily. | Amorini M | Annals of human genetics | 2015 | PMID: 26096904 |
Spectrum and frequency of GJB2 mutations causing deafness in the northwest of Iran. | Bonyadi MJ | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24529908 |
Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. | Dalamón V | Molecular biology reports | 2013 | PMID: 24158611 |
Etiologic diagnosis of nonsyndromic genetic hearing loss in adult vs pediatric populations. | King PJ | Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2012 | PMID: 22785241 |
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 |
Vestibular dysfunction in DFNB1 deafness. | Dodson KM | American journal of medical genetics. Part A | 2011 | PMID: 21465647 |
Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia. | Dzhemileva LU | Journal of human genetics | 2010 | PMID: 20739944 |
Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling. | Batissoco AC | Ear and hearing | 2009 | PMID: 19125024 |
A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. | Putcha GV | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17666888 |
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 |
Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. | Shahin H | Human genetics | 2002 | PMID: 11935342 |
A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non-syndromic deafness: A novel founder mutation in Ashkenazi Jews. | Lerer I | Human mutation | 2001 | PMID: 11668644 |
Connexin 26 studies in patients with sensorineural hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11556849 |
Nonradioactive detection of the common Connexin 26 167delT and 35delG mutations and frequencies among Ashkenazi Jews. | Dong J | Molecular genetics and metabolism | 2001 | PMID: 11386851 |
Contribution of connexin 26 mutations to nonsyndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. | Lerer I | American journal of medical genetics | 2000 | PMID: 11074495 |
The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. | Sobe T | Human genetics | 2000 | PMID: 10982182 |
Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. | Griffith AJ | American journal of human genetics | 2000 | PMID: 10903123 |
Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene mutations--molecular and audiological findings. | Mueller RF | International journal of pediatric otorhinolaryngology | 1999 | PMID: 10596881 |
High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. | Sobe T | American journal of medical genetics | 1999 | PMID: 10508996 |
Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). | Cohn ES | Pediatrics | 1999 | PMID: 10049954 |
Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. | Morell RJ | The New England journal of medicine | 1998 | PMID: 9819448 |
Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. | Zelante L | Human molecular genetics | 1997 | PMID: 9285800 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e530bac1-eebd-46fc-a983-e936764ec5dc | - | - | - | - |
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Text-mined citations for rs80338942 ...
HelpRecord last updated May 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.