13-20189546-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 14P and 8B. PM3BA1PS4PVS1

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

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:87O: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 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 rank MANE Protein UniProt
GJB2NM_004004.6 linkc.35delG p.Gly12ValfsTer2 frameshift_variant Exon 2 of 2 ENST00000382848.5 NP_003995.2 P29033H9U1J4
GJB2XM_011535049.3 linkc.35delG p.Gly12ValfsTer2 frameshift_variant Exon 2 of 2 XP_011533351.1 P29033H9U1J4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB2ENST00000382848.5 linkc.35delG p.Gly12ValfsTer2 frameshift_variant Exon 2 of 2 1 NM_004004.6 ENSP00000372299.4 P29033
GJB2ENST00000382844.2 linkc.35delG p.Gly12ValfsTer2 frameshift_variant Exon 1 of 1 6 ENSP00000372295.1 P29033

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:87Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:34Other:1
Sep 28, 2018
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MĂĽnchen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 14, 2016
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 05, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 03, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jul 18, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM3_VS, PS4 -

Jul 18, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 08, 2018
Center of Genomic medicine, Geneva, University Hospital of Geneva
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified in compound heterozygosity with a second variant in GJB2 in 2 different male patients with congenital bilateral moderate hearing loss. -

Feb 01, 2022
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 20, 2015
Division of Human Genetics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

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). -

Mar 19, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

We found this variant in a patient with hearing impairment in a homozygous state. -

Aug 08, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 28, 2021
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 23, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PVS1,PM3_VSTR,PS4 -

-
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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). -

Feb 26, 2019
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control

- -

May 09, 2017
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: flagged submission
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are mechanisms of disease in this gene. Whilst loss of function has been demonstrated for protein truncating variants, the gene mechanism for missense variants is not well established, although loss of function and dominant negative have been suggested (PMID: 19384972; PMID: 28428247). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423) (I) 0112 - Variants in this gene are known to have reduced penetrance, reported to be associated with the p.M34T and p.V37I missense variants (PMID: 31160754). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1717 heterozygotes, 10 homozygotes). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many downstream protein truncating variants have been reported as pathogenic (ClinVar; Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reviewed by expert panel to be pathogenic and is known to have variable expressivity, ranging from mild to profound deafness (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 08, 2023
Diagnostics Centre, Carl Von Ossietzky University Oldenburg
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 26, 2018
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PS3, PM1, PP5 -

Oct 18, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 26, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 02, 2023
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 23, 2022
UAEU Genomics Laboratory, United Arab Emirates University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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. -

Jan 10, 2023
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong -

May 11, 2023
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 04, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 04, 2023
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence variant is a single nucleotide deletion (delG) in exon 2 of 2 of GJB2 and results in a premature termition sigl 2 codons downstream of the frameshift introduced at the Gly12 residue. The c.35del allele may be referred to as 35delG in the literature and online databases. This variant generates a non-functiol allele through either the expression of a truncated protein or a loss of Connexin 26 expression due to nonsense mediated decay (PMID: 12176036). This variant is present in 0.6% of control population datasets (gnomAD database, 1737 of 280696, 0.62%) and is one of the most frequent alleles associated with Connexin 26-related non-syndromic hearing loss (PMID: 12176036, 16650073, 12172392). This variant has been observed in both the homozygous and compound heterozygous state in individuals affected with hearing loss (PMID: 12176036, 16650073, 12172392, 19371219, 26969326) and has been assessed as pathogenic by an expert panel since 2019 (ClinGen Hearing Loss Variant Curation Expert Panel, accession: SCV000840537.3). Based on this evidence, we consider this a pathogenic variant. ACMG Criteria: PM3, PS4, PVS1 -

Jun 24, 2021
Clinical Genomics Laboratory, Stanford Medicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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] -

Nov 24, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 11, 2024
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:18
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 11, 2023
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Nov 16, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 04, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 gene product 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. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital TĂĽbingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 04, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1 -

Nov 24, 2014
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 03, 2015
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 26, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The GJB2 c.35del; p.Gly12ValfsTer2 variant (rs80338939, ClinVar Variation ID 17004) is the most common pathogenic GJB2 variant found among individuals with European ancestry (Estivill 1998, Gasparini 2000, Putcha 2007). It has been reported in both homozygous and compound heterozygous state in individuals with autosomal recessive nonsyndromic hearing loss with severity ranging from mild to profound (Alkhidir 2024, Estivill 1998, Yan 2024). This variant is found in the general population with an overall allele frequency of 0.62% (1737/280696 alleles, including 10 homozygotes) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro expression studies with mutant protein demonstrate a complete loss of connexin 26 in transfected cells (D'Andrea 2002). Based on available information, this variant is considered to be pathogenic. References: Alkhidir S et al. The genetic basis and the diagnostic yield of genetic testing related to nonsyndromic hearing loss in Qatar. Sci Rep. 2024 Feb 20. PMID: 38378725. D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23. PMID: 12176036. Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7. 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. PMID: 10713883. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul. PMID: 17666888. Yan D et al. Etiologic Diagnosis of Genetic Hearing Loss in an Ethnically Diverse Deafness Cohort. Audiol Neurootol. 2024 Aug 23. PMID: 39182490. -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 15, 2019
Molecular Genetics laboratory, Necker Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 16, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3_very_strong, PS4, PVS1 -

Hearing impairment Pathogenic:6
Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 12, 2021
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1_Strong, PS3_Strong -

Jan 29, 2021
Yale Center for Mendelian Genomics, Yale University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hearing loss, autosomal recessive Pathogenic:3Other:1
-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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. -

-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Nov 08, 2024
Center for Statistical Genetics, Columbia University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Sep 21, 2016
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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:3
Oct 31, 2014
Division of Human Genetics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Dec 10, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 06, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

GJB2-related disorder Pathogenic:3
Sep 04, 2024
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PS4, PM3_Very Strong -

Sep 10, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Jan 01, 2024
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM3_VS, PS4, BA1 -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3
Sep 13, 2021
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 08, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 11, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nonsyndromic genetic hearing loss Pathogenic:2
Aug 31, 2020
INGEBI, INGEBI / CONICET
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS, PS4 -

Sep 20, 2018
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

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. -

Knuckle pads, deafness AND leukonychia syndrome Pathogenic:2
-
Genomics England Pilot Project, Genomics England
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 25, 2021
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Bilateral sensorineural hearing impairment;C1384666:Hearing impairment Pathogenic:1
Apr 12, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hearing loss Pathogenic:1
Feb 22, 2017
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Dec 02, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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&rsquo;-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
Oct 05, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Bilateral sensorineural hearing impairment Pathogenic:1
Oct 01, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Deafness Pathogenic:1
Sep 02, 2021
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
Institute of Human Genetics, University Hospital of Duesseldorf
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Bilateral conductive hearing impairment;C1384666:Hearing impairment Pathogenic:1
Jan 13, 2015
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe sensorineural hearing impairment Pathogenic:1
Jan 04, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Ear malformation Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1
Jun 23, 2022
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.35delG variant in GJB2 is known to be pathogenic with many supporting publications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. -

Hereditary palmoplantar keratoderma Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PVS1_PM3_VertStrong -

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