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Variant summary
Our verdict is Pathogenic. Variant got 6 ACMG points: 14P and 8B. PVS1PM3BA1PS4
This summary comes from the ClinGen Evidence Repository: The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established 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:26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID:26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), 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 hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127023/MONDO:0019497/005
Frequency
Genomes: đť‘“ 0.0063 ( 4 hom., cov: 32)
Exomes đť‘“: 0.0071 ( 34 hom. )
Consequence
GJB2
NM_004004.6 frameshift
NM_004004.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.85
Genes affected
GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 6 ACMG points.
PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJB2 | NM_004004.6 | c.35del | p.Gly12ValfsTer2 | frameshift_variant | 2/2 | ENST00000382848.5 | NP_003995.2 | |
| GJB2 | XM_011535049.3 | c.35del | p.Gly12ValfsTer2 | frameshift_variant | 2/2 | XP_011533351.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GJB2 | ENST00000382848.5 | c.35del | p.Gly12ValfsTer2 | frameshift_variant | 2/2 | 1 | NM_004004.6 | ENSP00000372299 | P1 | |
| GJB2 | ENST00000382844.2 | c.35del | p.Gly12ValfsTer2 | frameshift_variant | 1/1 | ENSP00000372295 | P1 |
Frequencies
GnomAD3 genomes 0.00627 AC: 952AN: 151764Hom.: 4 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:82Other:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:31Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 28, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12176036, PS3_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 25999548, 26969326, PS4_S). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000017004, PMID:9285800, 3billion dataset). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 26445815, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Mar 20, 2015 | The GJB2 variant (c.35delG, p.Gly12Valfs*2) identified in this patient is a frameshift variant, reported to be the most common pathogenic variant in individuals with European ancestry (Carrasquillo et al. 1997, PMID: 9328482; Denoyelle et al. 1997, PMID: 9336442; Zelante et al. 1997, PMID: 9285800; Green et al. 1999, PMID: 10376574; Gasparini et al. 2000, PMID: 10713883; Kenneson et al. 2002, PMID: 12172392; Bouwer et al. 2007, PMID: 18294064). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | NM_004004.5(GJB2):c.35delG(aka p.G12Vfs*2) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 12176036, 24158611, 19371219, 15967879, 16380907. Classification of NM_004004.5(GJB2):c.35delG(aka p.G12Vfs*2) 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. - |
| Pathogenic, criteria provided, single submitter | research | UAEU Genomics Laboratory, United Arab Emirates University | Mar 23, 2022 | The frameshift deletion NM_004004.6(GJB2):c.35delG (p.Gly12Valfs*2) is reported to be the most common pathogenic variant in GJB2 associated with Autosomal Recessive Deafness 1A (DFNB1A) across different ethnic groups and reported in homozygous and compound heterozygous states (PubMed: 9285800, 10422812, 10713883, 11313751, 11483639, 26445815). This variant has been curated as Pathogenic by ClinGen hearing loss Expert panel members (PMID: 30311386). Though this variant is observed in 1027/111668 (0.92%) alleles in the gnomAD database, studies suggests that the carrier frequency of this variant can reach up to 2%-4% (PMID: 16380907). The p.Gly12Valfs*2 variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. Published in vitro functional studies demonstrated that the variation leads to the absence of functional protein and activity (PubMed: 12176036). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 08, 2017 | Variant summary: The GJB2 c.35delG (p.Gly12Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.71G>A [p.Trp24X], c.131G>A [p.Trp44X], and c.167delT [p.Leu56fs). This variant was found in 733/122042 control chromosomes (3 homozygotes) including ExAC at a frequency of 0.0060061, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is known to be the most common pathogenic GJB2 variant worldwide that causes autosomal recessive nonsyndromic hearing loss. Immunochemistry studies showed that the variant does not produce detectable protein and prevents normal intercellular molecular transfer (D'Andrea_BBRC_2002). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 19, 2021 | We found this variant in a patient with hearing impairment in a homozygous state. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 18, 2024 | PVS1, PM3_VS, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 23, 2024 | Criteria applied: PVS1,PM3_VSTR,PS4 - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Nov 08, 2018 | This variant was identified in compound heterozygosity with a second variant in GJB2 in 2 different male patients with congenital bilateral moderate hearing loss. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 20, 2017 | A homozygous deletion variant was identified, NM_004004.5(GJB2):c.35delG in exon 2 of the GJB2 gene.This deletion creates a frameshift from amino acid position 12, introducing a stop codon 2 residues downstream, NP_003995.2(GJB2):p.(Gly12Valfs*2). This results in loss of protein function through truncation (majority of the protein).This variant is present in the gnomAD population database at a frequency of 0.6%. It has been previously reported to be the most common pathogenic variant in deaf individuals with European ancestry (ClinVar). In addition, other truncating variants downstream of c.35delG in GJB2 have been reported as pathogenic in individuals with deafness (ClinVar). Based on current information, this variant has been classified as PATHOGENIC. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 14, 2016 | The c.35delG (p.Gly12Valfs*2) frameshift variant introduces a premature stop codon, leading to the truncation of the Connexin 26 protein. The c.35delG variant represents the most common pathogenic variant in Caucasian patients with genetic sensorineural deafness (Carrasquillo et al. 1997; Denoyelle et al. 1997; Zelante et al. 1997; Green et al. 1999; Gasparini et al. 2000; Kenneson et al. 2002; Bouwer et al. 2007). Therefore, this collective evidence supports the classification of the c.35delG (p.Gly12Valfs*2) as a Pathogenic variant for Nonsyndromic hearing loss. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MĂĽnchen | Sep 28, 2018 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 18, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 04, 2018 | The GJB2 c.35delG (p.Gly12ValfsTer2) variant, which results in a frameshift and is predicted to result in premature termination of the protein, is one of the most common variants associated with the recessive form of nonsyndromic hearing loss, DFNB1, with more than half of all persons of northern European ancestry with two identifiable GJB2 mutations being homozygous for this variant (Scott et al. 1998). Across a small selection of the available literature, the p.Gly12ValfsTer2 variant has been identified in a homozygous state in 89 individuals with hearing loss, in a compound heterozygous state in 23 affected individuals, and in a heterozygous state in 11 affected individuals in whom a second variant was not identified (Zelante et al. 1997; Estivill et al. 1998; Murgia et al. 1999; Snoeckx et al. 2005). The p.Gly12ValfsTer2 variant was identified in a total of ten of 800 control chromosomes and is reported at a frequency of 0.0152 in the Utah residents with Northern and Western European ancestry population of the 1000 Genomes Project which is consistent with the carrier frequency for p.Gly12ValfsTer2 (Snoeckx et al. 2005). Based on the potential impact of frameshift variants and the evidence from the literature the p.Gly12ValfsTer2 variant is classified as pathogenic for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Feb 01, 2022 | - - |
| Pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The GJB2 c.35delG (p.G12fs) frameshift variant is reported as the most common pathogenic variant associated with autosomal recessive nonsyndromic hearing loss (PMID: 9285800; 9328482; 9819448; 12176036; 20301449). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jun 26, 2018 | PVS1, PS3, PM1, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostics Centre, Carl Von Ossietzky University Oldenburg | Nov 08, 2023 | The variant GJB2: c.35delG, p.Gly12Valfs*2, which is located in the coding exon 2 of the GJB2 gene, results from a deletion of a base at nucleotide position c.35. The variant causes a frameshift that results in the replace of a glycine by a valine at protein position 12, followed by a premature translation stop codon after two amino acids. Degradation of the truncated gene product due to non-sense mediated decay is not predicted. However, a large part of the protein is lost, including the functionally relevant connexin domain.The variant was described in an Italian study as the most common GJB2 variant associated with autosomal recessive non-syndromic hearing loss (PMID: 12176036). Multiple studies showed an increased prevalence on individuals affected with hearing loss (PMID: 26969326, 25999548). A cell culture-based functional study showed that the altered gene product is no longer detectable and leads to a loss of function of GJB2 (PMID: 12176036). The variant is not considered rare in the overall population (allele frequency= 0.007050 in gnomAD, v4.1.0). The variant has been consistently classified as Pathogenic in more than 80 entries in ClinVar (ClinvarID: 17004). The ClinGen Expert panel for hearing disorders classified this variant as Pathogenic despite the comparatively high allele frequency. In summary, the variant is classified as Pathogenic. - |
| Pathogenic, flagged submission | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Jun 24, 2021 | The p.Gly12Valfs*2 variant in the GJB2 gene is a well reported cause of nonsyndromic hearing loss. This variant was determined to be in trans with other pathogenic variants (p.Val37Ile, p.Met34Thr), consistent with autosomal recessive inheritance (Sloan-Heggen et al., 2016). The presence of this variant with an established disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Gly12Valfs*2 variant has also been identified in 1,217/127,068 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is consistent with a recessive carrier frequency for hearing loss. This variant results in a 1 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 2 amino acids downstream. Loss of function is an established mechanism of disease for the GJB2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Gly12Valfs*2 variant as pathogenic for autosomal recessive nonsyndromic hearing loss based on the information above. [ACMG evidence codes used: PVS1; PM3_verystrong] - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 10, 2023 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Integrating Genomics into Medicine, Frazer Institute, University Of Queensland | Jun 02, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 11, 2023 | - - |
not provided Pathogenic:19
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 04, 2016 | The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2021 | Case control studies suggest this variant is associated with hearing loss; allele frequency of the variant is significantly higher in individuals with hearing loss compared to individuals in the general population (Tsukada et al., 2015; Sloan-Heggen et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 214 amino acids are lost (Stenson et al., 2014); In vitro studies demonstrate that the c.35delG variant results in loss of connexin 26 function (D'Andrea et al., 2002); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840537.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 20815033, 22975760, 26896187, 29234782, 9819448, 18985073, 25262649, 12833397, 16088916, 21465647, 15070423, 20073550, 19925344, 20739944, 23489192, 27316387, 17666888, 16222667, 27843504, 12189487, 14738110, 25266519, 9285800, 27153395, 26990548, 19274344, 27177047, 25533962, 29501291, 29293505, 29431110, 29016196, 28281779, 17431919, 12169891, 12172392, 30609409, 30730013, 30094485, 29372807, 29542069, 29086887, 30168495, 30390570, 30431684, 31163360, 29907799, 30055715, 31028937, 31370293, 31162818, 30344259, 31564438, 31130284, 31541171, 32279305, 31827275, 31980526, 31160754, 30275481, 10782932, 32747562, 33443819, 14759569, 33096615, 29871260, 33297549, 12068628, 33466560, 33105617, 32067424, 32853555, 32860223, 11355484, 32842620, 31078570, 10713883, 12176036, 26969326, 25999548) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 16, 2023 | PM3_very_strong, PS4, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital TĂĽbingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 03, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 16, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 11, 2023 | This variant is expected to result in the loss of a functional protein. This variant is one of the most common variants associated with the recessive form of nonsyndromic hearing loss, DFNB1 (PMID: 20301449), and so therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is also referred to as 35delG, and sometimes 30delG, in published literature. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. In vitro studies demonstrate this variant results in loss of connexin 26 function (PMID: 12176036). - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 07, 2023 | The GJB2 c.35delG; p.Gly12ValfsTer2 variant (rs80338939) is the most common pathogenic GJB2 variant found among individuals with European ancestry (Estivill 1998, Gasparini 2000). It has been described in the homozygous and compound heterozygous state in individuals affected with autosomal recessive nonsyndromic hearing loss with severity ranging from mild to profound (Estivill 1998, Gasparini 2000, Putcha 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17004) and is observed in the general population at an overall frequency of 0.6% (1737/280696 alleles, 10 homozygotes) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, and in vitro functional studies demonstrate a loss of connexin 26 function (D’Andrea 2002). Based on available information, this variant is considered pathogenic. References: D’Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. PMID: 12176036 Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7;351(9100):394-8. PMID: 9482292 Gasparini P et al. High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. Eur J Hum Genet. 2000 Jan;8(1):19-23. PMID: 10713883 Putcha G et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. PMID: 17666888 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Gly12Valfs*2) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 215 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338939, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 9285800, 9328482, 12239718). It is commonly reported in individuals of European ancestry (PMID: 10751669, 12172392, 12176036, 12239718, 19925344). ClinVar contains an entry for this variant (Variation ID: 17004). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GJB2 function (PMID: 12176036). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics laboratory, Necker Hospital | Feb 15, 2019 | - - |
Hearing impairment Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Jan 29, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PVS1_Strong, PS3_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
| Pathogenic, no assertion criteria provided | research | Center for Statistical Genetics, Columbia University | Nov 22, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Sep 13, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 11, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1. This variant was detected in homozygous state. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2016 | - - |
Hearing loss, autosomal recessive Pathogenic:2Other:1
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Sep 21, 2016 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant identified in multiple participants. Variant interpreted as Pathogenic and reported on 10-31-2014 by Lab or GTR ID 50489, reported on 03-17-2020 by Lab or GTR ID 21766, and reported on 11/16/2015 by GTR ID 165021. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 10, 2021 | GJB2 NM_004004.5 exon 2 p.Gly12Valfs*2 (c.35delG): This variant is reported to be one of the most common pathogenic GJB2 variants; it has been reported in the literature in the homozygous or compound heterozygous state in numerous individuals with autosomal recessive nonsyndromic hearing loss (Carrasquillo 1997 PMID: 9328482; Denoyelle 1997 PMID: 9336442; Zelante 1997, PMID: 9285800; Green 1999 PMID: 10376574; Gasparini 2000 PMID: 10713883; Kenneson 2002 PMID: 12172392; Bouwer 2007 PMID: 18294064). This variant is present in 0.9% (1217/127068) of European alleles in the Genome Aggregation Database, including 4 homozygotes (http://gnomad.broadinstitute.org/variant/13-20763685-AC-A). Please note, disease causing variants may be present in control databases, reflective of the general population, carrier frequency, and/or variable expressivity. This variant is present in ClinVar, with multiple reporting labs classifying this variant as pathogenic (Variation ID:17004). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies predict that this variant will impact the protein and result in loss of connexin 26 function (D'Andrea 2002 PMID: 12176036). However, these studies may not accurately represent in vivo biological function. This variant is a deletion of one nucleotide and creates a premature stop codon 2 amino acids downstream from this location, which results in an absent or abnormal protein. Loss of function variants are commonly reported in association with disease for this gene (Choi 2011 PMID:21298213). In summary, this variant is classified as pathogenic based on the data above. - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Oct 31, 2014 | - - |
Nonsyndromic genetic hearing loss Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Aug 31, 2020 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS, PS4 - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Sep 20, 2018 | The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established 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: 26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), 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 hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. - |
Bilateral sensorineural hearing impairment;C1384666:Hearing impairment Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 12, 2014 | - - |
Hearing loss Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Feb 22, 2017 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2022 | The c.35delG (p.G12Vfs*2) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, consists of a deletion of one nucleotide at position 35, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. The GJB2 gene has a single coding exon, so while the alteration is truncating, the mRNA is not predicted to undergo nonsense mediated decay (NMD) and a truncated mutant protein could still be expressed. Premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3’-most exon-exon junction usually fail to elicit NMD (Maquat, 2004). The exact functional impact of these altered amino acids is unknown at this time; however, this alteration and additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing (Roux, 2004). Based on data from gnomAD, the - allele has an overall frequency of 0.619% (1737/280696) total alleles studied. The highest observed frequency was 0.958% (1217/127068) of European (non-Finnish) alleles. The c.35delG variant is the most common GJB2 pathogenic variant among Caucasians individuals, and has been reported in patients with mild to profound hearing loss of multiple ethnicities (Denoyelle, 1997; Gasparini, 2000; Gualandi, 2002; Roux, 2004; Hilgert, 2009; Mahdieh, 2016; Zytsar, 2018). Additionally, this variant was observed in trans with p.N176D in multiple families with syndromic hearing loss with ectodermal involvement (Youssefian, 2018; Youssefian, 2022). Functional studies show an absence of protein expression and reduced intercellular diffusion of dye in vitro (D'Andrea, 2002). Based on the available evidence, this alteration is classified as pathogenic. - |
Deafness, digenic, GJB2/GJB6 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2012 | - - |
Bilateral sensorineural hearing impairment Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 01, 2014 | - - |
GJB2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2024 | The GJB2 c.35delG variant is predicted to result in a frameshift and premature protein termination (p.Gly12Valfs*2). This variant has been reported to be one of the most common causative variants for autosomal recessive nonsyndromic hearing loss and deafness (Wilcox et al. 2000. PubMed ID: 10830906; D'Andrea et al. 2002. PubMed ID: 12176036; Chan et al. 2010. PubMed ID: 20154630; Dzhemileva et al. 2010. PubMed ID: 20739944). This variant is interpreted as pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Sep 02, 2021 | The c.35delG variant is a deletion of one guanine in a sequence of six guanines in the GJB2 coding sequence leading to premature chain termination at the twelfth amino acid of the Cx26 protein p.(Gly12Valfs*2) - PVS_strong. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16773579; 12176036) - PS3_supporting. This variant is the most common in Caucasian populations and is described as pathogenic in the specialized literature, being one of the most common variant associated with non-syndromic deafness phenotype (ClinVar ID: 17004, ClinGen: CA127023, OMIM: 121011.0005, PMID: 20301449, 16773579, 34440441) – PS4. The c.35delG was detected in trans with a pathogenic variant (PMID: 21220926, 26096904, 24039984, 14694360, 34440441, 16849369) – PM3_very strong; and co-segregated with deafnes in multiple affected family members (PMID: 16773579, 24039984, 14694360) – PP1. This variant is observed in the general population (rs80338939 - gnomAD 0,006 frequency; ABraOM 0,0098 frequency - http://abraom.ib.usp.br/). In summary, the currently available evidence indicates that the variant is pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 104 Pathogenic:1
| Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Bilateral conductive hearing impairment;C1384666:Hearing impairment Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 13, 2015 | - - |
GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
Knuckle pads, deafness AND leukonychia syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
Severe sensorineural hearing impairment Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 04, 2016 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2022 | The c.35delG variant in GJB2 is known to be pathogenic with many supporting publications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. - |
Ear malformation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
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