Menu
GeneBe

rs80338939

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_004004.6(GJB2):c.35del(p.Gly12ValfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00705 in 1,613,482 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0063 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0071 ( 34 hom. )

Consequence

GJB2
NM_004004.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:80O:2

Conservation

PhyloP100: 7.85
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 265 pathogenic variants in the truncated region.
PP5
Variant 13-20189546-AC-A is Pathogenic according to our data. Variant chr13-20189546-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 17004.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-20189546-AC-A is described in Lovd as [Likely_pathogenic]. Variant chr13-20189546-AC-A is described in Lovd as [Pathogenic]. Variant chr13-20189546-AC-A is described in Lovd as [Pathogenic]. Variant chr13-20189546-AC-A is described in Lovd as [Pathogenic]. Variant chr13-20189546-AC-A is described in Lovd as [Likely_pathogenic].
BS2
High Homozygotes in GnomAd at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB2NM_004004.6 linkuse as main transcriptc.35del p.Gly12ValfsTer2 frameshift_variant 2/2 ENST00000382848.5
GJB2XM_011535049.3 linkuse as main transcriptc.35del p.Gly12ValfsTer2 frameshift_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB2ENST00000382848.5 linkuse as main transcriptc.35del p.Gly12ValfsTer2 frameshift_variant 2/21 NM_004004.6 P1
GJB2ENST00000382844.2 linkuse as main transcriptc.35del p.Gly12ValfsTer2 frameshift_variant 1/1 P1

Frequencies

GnomAD3 genomes
AF:
0.00627
AC:
952
AN:
151764
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00124
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.00584
Gnomad ASJ
AF:
0.00403
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.000833
Gnomad FIN
AF:
0.00956
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00980
Gnomad OTH
AF:
0.0106
GnomAD3 exomes
AF:
0.00597
AC:
1488
AN:
249362
Hom.:
7
AF XY:
0.00599
AC XY:
808
AN XY:
134954
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00480
Gnomad ASJ exome
AF:
0.00318
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000817
Gnomad FIN exome
AF:
0.00808
Gnomad NFE exome
AF:
0.00920
Gnomad OTH exome
AF:
0.00718
GnomAD4 exome
AF:
0.00713
AC:
10423
AN:
1461600
Hom.:
34
Cov.:
32
AF XY:
0.00701
AC XY:
5100
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.00128
Gnomad4 AMR exome
AF:
0.00494
Gnomad4 ASJ exome
AF:
0.00356
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000592
Gnomad4 FIN exome
AF:
0.00947
Gnomad4 NFE exome
AF:
0.00818
Gnomad4 OTH exome
AF:
0.00652
GnomAD4 genome
AF:
0.00627
AC:
952
AN:
151882
Hom.:
4
Cov.:
32
AF XY:
0.00601
AC XY:
446
AN XY:
74244
show subpopulations
Gnomad4 AFR
AF:
0.00123
Gnomad4 AMR
AF:
0.00583
Gnomad4 ASJ
AF:
0.00403
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.000833
Gnomad4 FIN
AF:
0.00956
Gnomad4 NFE
AF:
0.00980
Gnomad4 OTH
AF:
0.0104
Alfa
AF:
0.00556
Hom.:
0
Bravo
AF:
0.00549
EpiCase
AF:
0.00916
EpiControl
AF:
0.00842

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:80Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:30Other:1
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyMay 11, 2023- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneOct 28, 2021- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaDec 04, 2018The 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 submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundJun 20, 2023- -
Pathogenic, criteria provided, single submitterresearchUNC 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 submitterresearchUAEU Genomics Laboratory, United Arab Emirates UniversityMar 23, 2022The 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 providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
Pathogenic, flagged submissionclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaMay 09, 2017- -
Pathogenic, criteria provided, single submitterclinical testingDaryl Scott Lab, Baylor College of MedicineFeb 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJun 20, 2017A 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, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaNov 08, 2018This 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 submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinJan 10, 2023ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong -
Pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022Frameshift: 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 submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenSep 28, 2018- -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaMar 20, 2015The 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 submitterclinical testingGenome-Nilou LabMar 19, 2021We found this variant in a patient with hearing impairment in a homozygous state. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJun 20, 2023Criteria applied: PM3_VSTR,PVS1_STR -
Pathogenic, criteria provided, single submitterclinical testingIntegrating Genomics into Medicine, Frazer Institute, University Of QueenslandJun 02, 2023- -
Pathogenic, no assertion criteria providedcase-controlGenetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General HospitalFeb 26, 2019- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensJun 26, 2018PVS1, PS3, PM1, PP5 -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 14, 2016The 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, no assertion criteria providedliterature onlyOMIMOct 05, 2012- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 26, 2024- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 08, 2017Variant 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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, no assertion criteria providedclinical testingClinical Genomics Program, Stanford MedicineJun 24, 2021The 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] -
not provided Pathogenic:19
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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, criteria provided, single submitterclinical testingAthena DiagnosticsJan 11, 2023This 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, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalDec 17, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsNov 24, 2014- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalSep 03, 2015- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 04, 2016The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1 -
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics laboratory, Necker HospitalFeb 15, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 04, 2021Case 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 submitterclinical testingLaboratoire de Génétique Moléculaire, CHU Bordeaux-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 07, 2023The 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, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 16, 2023PM3_very_strong, PS4, PVS1 -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 19, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaNov 16, 2015- -
Hearing impairment Pathogenic:7
Pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityJan 29, 2021- -
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de Bourgogne-- -
Pathogenic, no assertion criteria providedresearchCenter for Statistical Genetics, Columbia UniversityNov 22, 2018- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Otolaryngology – Head & Neck Surgery, Cochlear Implant CenterApr 12, 2021PVS1_Strong, PS3_Strong -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingCounsylMar 08, 2016- -
Likely pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinSep 13, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJun 11, 2019This 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. -
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 submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoDec 10, 2021GJB2 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 providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaOct 31, 2014- -
Nonsyndromic genetic hearing loss Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingINGEBI, INGEBI / CONICETAug 31, 2020Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS, PS4 -
Pathogenic, reviewed by expert panelcurationClinGen Hearing Loss Variant Curation Expert PanelSep 20, 2018The 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. -
Hearing loss, autosomal recessive Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversitySep 21, 2016- -
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Bilateral sensorineural hearing impairment;C1384666:Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaApr 12, 2014- -
Hearing loss Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalFeb 22, 2017- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 02, 2022The 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 providedliterature onlyOMIMOct 05, 2012- -
Bilateral sensorineural hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaOct 01, 2014- -
GJB2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 03, 2023The 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 submitterclinical testingBaylor Genetics-- -
Deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingDASASep 02, 2021The 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 submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
Bilateral conductive hearing impairment;C1384666:Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 13, 2015- -
Knuckle pads, deafness AND leukonychia syndrome Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGenomics 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 05, 2021- -
Severe sensorineural hearing impairment Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 04, 2016- -
Ear malformation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 23, 2022The c.35delG variant in GJB2 is known to be pathogenic with many supporting publications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. -
Nonsyndromic Hearing Loss, Recessive Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338939; hg19: chr13-20763685; API