ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.-23+1G>A
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.-23+1G>A
Variation ID: 17029 Accession: VCV000017029.93
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20192782 (GRCh38) [ NCBI UCSC ] 13: 20766921 (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 May 5, 2014 Oct 8, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.-23+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000013.11:g.20192782C>T NC_000013.10:g.20766921C>T NG_008358.1:g.5194G>A LRG_1350:g.5194G>A LRG_1350t1:c.-23+1G>A - Protein change
- Other names
- IVS1+1G>A
- IVS1DS, G-A, +1
- Canonical SPDI
- NC_000013.11:20192781:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00017
Trans-Omics for Precision Medicine (TOPMed) 0.00018
1000 Genomes Project 30x 0.00062
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
569 | 636 |
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 (15) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000018557.60 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2021 | RCV000146002.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV000211766.13 | |
Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000418755.52 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 14, 2017 | RCV000678858.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2021 | RCV000762908.11 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004401.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257033.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001291328.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001813995.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2022 | RCV003147300.9 | |
GJB2-related disorder
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Pathogenic (1) |
no assertion criteria provided
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May 1, 2024 | RCV004532386.2 |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003458323.1 | |
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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
(-)
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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: SCV001163373.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Feb 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156573.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022 |
Comment:
The GJB2 c.-23+1G>A variant (rs80338940), also known as IVS-1+1G>A, has been reported in individuals with autosomal recessive deafness (Barashkov 2011, Denoyelle 1999, Shahin 2002). Functional … (more)
The GJB2 c.-23+1G>A variant (rs80338940), also known as IVS-1+1G>A, has been reported in individuals with autosomal recessive deafness (Barashkov 2011, Denoyelle 1999, Shahin 2002). Functional characterization of the variant indicates an absence of detectable transcript in the patient (Shahin 2002). The variant is listed as pathogenic in ClinVar (Variation ID: 17029), and observed 5 times in the Genome Aggregation Database general population database (5/30850 alleles). The variant is located in the splice consensus site, and computational algorithms (GeneSplicer, Human Splicing Finder, MaxEntScan, MutationTaster, NetGene2, NNSplice, SpliceSiteFinder-like) predict the loss of the canonical splice donor. Based on the above information, the variant is classified as pathogenic. References: Barashkov N et al. Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect. J Hum Genet. 2011; 56(9):631-9. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999; 353(9161):1298-303. Shahin H et al. Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Hum Genet. 2002; 110(3):284-9. (less)
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Pathogenic
(Jul 11, 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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MGZ Medical Genetics Center
Accession: SCV002581008.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS3, PM3, PM2_SUP
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Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Mar 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003836380.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003922400.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 … (more)
A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 was detected. This variant has not been reported in the 1000 genomes and gnomdAD (v2) databases and has a minor allele frequency of 0.03% and 0.02% in the gnomAD (v3.1) and topmed databases, respectively. The in silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Hearing impairment (present)
Age: 30-39 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Likely pathogenic
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003936065.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 … (more)
A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 (c.-23+1G>A; ENST00000382848.5) was detected. The observed variant has previously been reported (as IVS1+1G>A) in patients affected with hearing loss [PMID: 27843504, ClinVar: VCV000017029.72]. This variant has not been reported in the 1000 genomes and gnomdAD (v2) databases and has a minor allele frequency of 0.03% and 0.02% in the gnomAD (v3.1) and topmed databases, respectively. The in-silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Hearing impairment (present)
Age: 30-39 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Autosomal recessive nonsyndromic hearing loss 104
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004177271.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Mar 26, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806709.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090001.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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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: SCV000193153.1
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: SCV000599720.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Number of individuals with the variant: 8
Observation 2:
Number of individuals with the variant: 3
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Pathogenic
(Oct 24, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698237.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The GJB2 c.-23+1G>A variant (alternatively also known as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, and -3172G>A) involves the alteration of the invariant splice donor site … (more)
Variant summary: The GJB2 c.-23+1G>A variant (alternatively also known as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, and -3172G>A) involves the alteration of the invariant splice donor site in intron 1. 5/5 splice prediction tools predict that this variant eliminates the 5' splicing donor site. The prediction result was confirmed by a functional study; RNA isolated from lymphocytes from the proband carrying c.-23-1G>A variant and subsequent sequencing of cDNA showed no transcript from this allele (Shahin_2002). This variant was found in 21/4256 control chromosomes at a frequency of 0.0049342, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported as one of the common pathogenic variants causing ARNSHL in literature with consistent genotype-phenotype data. The variant has also been postulated to originate from and to have a founder effect in central Asia (Barashkov_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 24, 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: SCV001194242.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_004004.5(GJB2):c.-23+1G>A is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 21776002. … (more)
NM_004004.5(GJB2):c.-23+1G>A is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 21776002. Classification of NM_004004.5(GJB2):c.-23+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Aug 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001433538.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.-23+1G>A variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.-23+1G>A variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This type of variant is predicted to generate a loss of the donor splicing site in GJB2 gene , which is a known mechanism of disease (PVS1). The c.-23+1G>A variant has been identified in trans with at least 4 pathogenic variants in hearing loss patients applying to PM3_VeryStrong rule (PMID: 10218527, 11313763, 16380907). It was demonstrated that this genetic variant disrupted splicing, yielding no detectable message by sequencing the cDNA from lymphoblastoid cell line of J3 from mutant allele, meeting PS3_Supporting criteria (PMID: 11935342). Therefore, the c.23-23+1G>A variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PVS1, PM3_VerySrong, PS3_Supporting) (less)
Number of individuals with the variant: 2
Clinical Features:
Congenital severe bilateral hearing loss (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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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: SCV001571780.2
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment:
PVS1_Strong, PS1_Strong, PM3_Moderate, BP4_Supporting
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Pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905675.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Sensorineural hearing loss disorder (present)
Sex: male
|
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Ear malformation
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755100.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Aug 01, 2020)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV002059940.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
GJB2 c.-23+1G>A is homozygous in a Palestinian child with severe to profound hearing loss (Abu Rayyan 2020). Based on analysis of RNA from the patient, … (more)
GJB2 c.-23+1G>A is homozygous in a Palestinian child with severe to profound hearing loss (Abu Rayyan 2020). Based on analysis of RNA from the patient, no transcript from the mutant allele was detectable (PMID: 11935342). The variant is not present in 1300 Palestinian controls and absent from gnomAD v2.1.1. (less)
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Pathogenic
(Jul 06, 2021)
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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: SCV000893318.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 03, 2021)
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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: SCV000516861.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate that this variant disrupts splicing … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate that this variant disrupts splicing and results in no gene transcription (Shahin et al., 2002); Also known IVS1+1G>A; This variant is associated with the following publications: (PMID: 24840842, 24959830, 25012701, 11935342, 31162818, 16650079, 32708339, 10218527, 24793888, 27843504, 27481527, 31160754, 21776002, 31980526, 32747562, 33096615, 29062245, 30030956, 30487145, 31346875, 31195736, 29907799, 30344259, 31541171, 30275481, 33105617) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 3A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003926486.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
A Heterozygous Splice site donor variant c.-23+1G>A in Exon 1 of the GJB2 gene that results in the amino acid substitution was identified. The observed … (more)
A Heterozygous Splice site donor variant c.-23+1G>A in Exon 1 of the GJB2 gene that results in the amino acid substitution was identified. The observed variant has a maximum allele frequency is novel in gnomAD exomes and 0.00019% in genomes, respectively. The severity of the impact of this variant on the protein is high, 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 [Variation ID: 17029]. The literature have been suggesting that, heterozygosity for a GJB2 or GJB6 mutation connotes carrier status for NSHL and rarely can cause autosomal dominant hearing loss by Vassos Neocleous et al., 2014. For these reasons, this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Apr 28, 2023)
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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
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003927247.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
This GJB2 canonical splice variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with autosomal recessive deafness 1A. This … (more)
This GJB2 canonical splice variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with autosomal recessive deafness 1A. This variant (rs80338940) is present in a large population dataset (gnomAD v3.1.2: 42/152092 total alleles; 0.03%; no homozygotes), and has been reported in ClinVar (Variation ID 17029). The variant destroys a canonical splice donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence1. We consider c.-23+1G>A in GJB2 to be pathogenic. (less)
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Pathogenic
(Jun 02, 2023)
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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
|
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935291.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
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Pathogenic
(Mar 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000841702.4
First in ClinVar: Mar 08, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population … (more)
This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). The variant is a common founder originating from Eastern Siberia (PMID: 21776002). This variant is also referred to as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, or -3172G>A in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. RNA studies performed on patient lymphocytes yielded no detectable transcript (PMID: 11935342). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024266.3
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
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000957075.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 1 of the GJB2 gene. It does not directly change the encoded amino acid sequence of the GJB2 protein. … (more)
This sequence change falls in intron 1 of the GJB2 gene. It does not directly change the encoded amino acid sequence of the GJB2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338940, gnomAD 0.03%). This variant has been observed in individual(s) with deafness (PMID: 10218527, 11935342, 21776002, 24840842, 24959830, 27481527, 27843504). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Yakut ancestry (PMID: 21776002). ClinVar contains an entry for this variant (Variation ID: 17029). Studies have shown that this variant alters GJB2 gene expression (PMID: 11935342). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061468.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The c.-23+1G>A variant in GJB2 has been reported in many probands with hearing loss (Denoyelle 1999 PMID: 10218527, Shahin 2002 PMID: 11935342, Sirmaci 2006 PMID: … (more)
The c.-23+1G>A variant in GJB2 has been reported in many probands with hearing loss (Denoyelle 1999 PMID: 10218527, Shahin 2002 PMID: 11935342, Sirmaci 2006 PMID: 17406097, Yuan 2010 PMID: 21122151, Barashkov 2011 PMID: 21776002). Most of these probands were homozygous or compound heterozygous. In addition, functional studies have shown that this variant disrupts splicing, yielding no detectable mRNA (Shahin 2002 PMID: 11935342). In summary, this variant meets our criteria to be classified as pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3. (less)
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Pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245656.25
First in ClinVar: May 09, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 01, 2011)
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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
|
OMIM
Accession: SCV000038839.7
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2020 |
Comment on evidence:
In a patient with sporadic nonsyndromic sensorineural deafness (DFNB1A; 220290), Denoyelle et al. (1999) identified compound heterozygosity for mutations in the GJB2 gene: a -3170G-A … (more)
In a patient with sporadic nonsyndromic sensorineural deafness (DFNB1A; 220290), Denoyelle et al. (1999) identified compound heterozygosity for mutations in the GJB2 gene: a -3170G-A transition (IVS1+1G-A), and the common 30delG (alternatively known as 35delG; 121011.0005). Cryns et al. (2004) observed 35delG/IVS1+1G-A compound heterozygotes to have significantly less severe hearing impairment compared to 35delG homozygotes. As the conclusion that there is no mRNA for the IVS1+1G-A mutation is based on a DNA sequencing result (Shahin et al., 2002), the presence of a very small amount of mRNA cannot be excluded, possibly providing an explanation for this discrepancy. Seeman and Sakmaryova (2006) identified compound heterozygosity for the IVS1+1G-A mutation and 35delG in 9 Czech patients with nonsyndromic hearing loss. Combined with other results from Czech individuals, the authors estimated that this splice site mutation represents 4% of pathogenic GJB2 mutations, making it the third most common GJB2 mutation in Czech patients with hearing loss. Barashkov et al. (2011) found homozygosity for the IVS1+1G-A mutation in 70 of 86 patients from the Yakut population isolate in eastern Siberia with nonsyndromic hearing impairment. Six patients were compound heterozygous for this mutation and another pathogenic GJB2 mutation. Audiometric examination was performed on 40 patients who were homozygous for the mutation. Most (85%) had severe to profound hearing impairment, 14% had moderate impairment, and 1% had mild hearing loss. There was some variability in hearing thresholds. The carrier frequency for this mutation in this population was estimated to be 11.7%, the highest among 6 eastern Siberian populations analyzed, and the mutation was estimated to be about 800 years old. The findings were consistent with a founder effect, and Barashkov et al. (2011) postulated a central Asian origin for this mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001975771.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(May 01, 2024)
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no assertion criteria provided
Method: clinical testing
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GJB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103054.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The GJB2 c.-23+1G>A variant is located in the 5' untranslated region. This variant is also described as c.-3170G>A or IVS1+1G>A and has been reported to … (more)
The GJB2 c.-23+1G>A variant is located in the 5' untranslated region. This variant is also described as c.-3170G>A or IVS1+1G>A and has been reported to be causative for autosomal recessive nonsyndromic hearing loss (Denoyelle et al. 1999. PubMed ID: 10218527; Barashkov et al. 2011. PubMed ID: 21776002; Barashkov et al. 2014. PubMed ID: 24959830). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed as pathogenic in ClinVar by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/17029/). This variant is interpreted as pathogenic. (less)
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pathologic
(Jul 14, 2011)
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no assertion criteria provided
Method: literature only
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DFNB 1 Nonsyndromic Hearing Loss and Deafness
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000041037.2
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2014 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Feb 11, 2015)
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no assertion criteria provided
Method: clinical testing
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Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV000223931.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Aug 14, 2017)
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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: SCV000805051.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: case-control
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
inherited
|
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902315.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 4
Clinical Features:
hearing loss (present)
Family history: yes
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001455338.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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non-syndromic autosomal recessive hearing loss
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479801.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001951168.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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 |
---|---|---|---|---|
GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss. | Adam MP | - | 2023 | PMID: 20301449 |
Selective Heterozygous Advantage of Carriers of с.-23+1G>A Mutation in GJB2 Gene Causing Autosomal Recessive Deafness 1A. | Solovyev AV | Bulletin of experimental biology and medicine | 2019 | PMID: 31346875 |
Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. | Richard EM | Human mutation | 2019 | PMID: 30303587 |
Rare compound heterozygosity involving dominant and recessive mutations of GJB2 gene in an assortative mating hearing impaired Indian family. | Pavithra A | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2017 | PMID: 27481527 |
Evaluation of electrocardiographic parameters in patients with hearing loss genotyped for the connexin 26 gene (GJB2) mutations. | Sanecka A | Brazilian journal of otorhinolaryngology | 2017 | PMID: 27177978 |
Relationship Between Patients with Clinical Auditory Neuropathy Spectrum Disorder and Mutations in Gjb2 Gene. | de Carvalho GM | The open neurology journal | 2016 | PMID: 27843504 |
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 |
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 |
Finding mutation within non-coding region of GJB2 reveals its importance in genetic testing of hearing loss in Iranian population. | Kashef A | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25555641 |
GJB2 c.-23+1G>A mutation is second most common mutation among Iranian individuals with autosomal recessive hearing loss. | Zeinali S | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2015 | PMID: 25012701 |
GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. | Hernández-Juárez AA | International journal of pediatric otorhinolaryngology | 2014 | PMID: 25288386 |
Spectrum of GJB2 mutations in Cypriot nonsyndromic hearing loss subjects. | Neocleous V | Journal of genetics | 2014 | PMID: 25189242 |
Age-Related Hearing Impairment (ARHI) associated with GJB2 single mutation IVS1+1G>A in the Yakut population isolate in Eastern Siberia. | Barashkov NA | PloS one | 2014 | PMID: 24959830 |
High incidence of GJB2 gene mutations among assortatively mating hearing impaired families in Kerala: future implications. | Pavithra A | Journal of genetics | 2014 | PMID: 24840842 |
Distribution and phenotype of GJB2 mutations in 102 Sicilian patients with congenital non syndromic sensorineural hearing loss. | Salvago P | International journal of audiology | 2014 | PMID: 24793888 |
Spectrum and frequency of GJB2 mutations causing deafness in the northwest of Iran. | Bonyadi MJ | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24529908 |
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 DFNB1 mutations in Slovak patients with non-syndromic hearing loss. | Minárik G | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22281373 |
Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association. | Matos TD | Genetics research international | 2011 | PMID: 22567369 |
Prevalence of IVS1+1G>A mutation among Iranian Azeri Turkish patients with autosomal recessive non-syndromic hearing loss (ARNSHL). | Bonyadi M | International journal of pediatric otorhinolaryngology | 2011 | PMID: 22000900 |
Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect. | Barashkov NA | Journal of human genetics | 2011 | PMID: 21776002 |
Prevalence of the GJB2 IVS1+1G >A mutation in Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of GJB2. | Yuan Y | Journal of translational medicine | 2010 | PMID: 21122151 |
GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf. | Tekin M | Annals of human genetics | 2010 | PMID: 20201936 |
Prevalence of DFNB1 mutations in Argentinean children with non-syndromic deafness. Report of a novel mutation in GJB2. | Gravina LP | International journal of pediatric otorhinolaryngology | 2010 | PMID: 20022641 |
GJB2 and GJB6 gene mutations found in Indian probands with congenital hearing impairment. | Padma G | Journal of genetics | 2009 | PMID: 20086291 |
GJB2 mutations in patients with nonsyndromic hearing loss from Croatia. | Sansović I | Genetic testing and molecular biomarkers | 2009 | PMID: 19814620 |
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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
The c.IVS1+1G>A mutation in the GJB2 gene is prevalent and large deletions involving the GJB6 gene are not present in the Turkish population. | Sirmaci A | Journal of genetics | 2006 | PMID: 17406097 |
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 |
Effects of GJB2 genotypes on the audiological phenotype: variability is present for all genotypes. | Hişmi BO | International journal of pediatric otorhinolaryngology | 2006 | PMID: 16712961 |
High prevalence of the IVS 1 + 1 G to A/GJB2 mutation among Czech hearing impaired patients with monoallelic mutation in the coding region of GJB2. | Seeman P | Clinical genetics | 2006 | PMID: 16650079 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Mutation analysis of the GJB2 (connexin 26) gene in Egypt. | Snoeckx RL | Human mutation | 2005 | PMID: 15954104 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India. | RamShankar M | Journal of medical genetics | 2003 | PMID: 12746422 |
Hearing loss: frequency and functional studies of the most common connexin26 alleles. | D'Andrea P | Biochemical and biophysical research communications | 2002 | PMID: 12176036 |
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 involving the connexin 30 gene in nonsyndromic hearing impairment. | del Castillo I | The New England journal of medicine | 2002 | PMID: 11807148 |
Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. | Marlin S | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11493200 |
Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. | Löffler J | European journal of human genetics : EJHG | 2001 | PMID: 11313763 |
Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. | Green GE | JAMA | 1999 | PMID: 10376574 |
Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. | Denoyelle F | Lancet (London, England) | 1999 | PMID: 10218527 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs80338940 ...
HelpRecord last updated Oct 13, 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.