Submissions for variant NM_004004.6(GJB2):c.35del (p.Gly12fs)

dbSNP: rs80338939

Total submissions: 86

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000211775	SCV000840537	pathogenic	Nonsyndromic genetic hearing loss	2018-09-20	reviewed by expert panel	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844702	SCV000061505	pathogenic	Rare genetic deafness	2022-06-23	criteria provided, single submitter	clinical testing	The c.35delG variant in GJB2 is known to be pathogenic with many supporting publications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago	RCV000146019	SCV000193171	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000018527	SCV000223930	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-03-14	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	RCV000080373	SCV000227317	pathogenic	not provided	2016-01-04	criteria provided, single submitter	clinical testing	The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000080373	SCV000257945	pathogenic	not provided	2015-11-16	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000080373	SCV000280697	pathogenic	not provided	2014-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000080373	SCV000321725	pathogenic	not provided	2021-11-04	criteria provided, single submitter	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)
Counsyl	RCV000411531	SCV000487402	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-03-08	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415181	SCV000492685	pathogenic	Bilateral sensorineural hearing impairment	2014-10-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000146019	SCV000492742	pathogenic	Hearing impairment	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415367	SCV000492743	pathogenic	Hearing impairment; Bilateral conductive hearing impairment	2015-01-13	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414886	SCV000492744	pathogenic	Hearing impairment; Bilateral sensorineural hearing impairment	2014-04-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000080373	SCV000603812	pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	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
Athena Diagnostics	RCV000080373	SCV000613516	pathogenic	not provided	2023-01-11	criteria provided, single submitter	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018527	SCV000698250	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-08-08	criteria provided, single submitter	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.
Ambry Genetics	RCV000623840	SCV000741869	pathogenic	Inborn genetic diseases	2022-12-02	criteria provided, single submitter	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’-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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000018527	SCV000746336	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-08-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000018527	SCV000915629	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-12-04	criteria provided, single submitter	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000018527	SCV000928370	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-06-26	criteria provided, single submitter	clinical testing	PVS1, PS3, PM1, PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV000080373	SCV000950817	pathogenic	not provided	2024-01-31	criteria provided, single submitter	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 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.
Mendelics	RCV000018527	SCV001138912	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000018527	SCV001149786	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-09-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004400	SCV001163372	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018527	SCV001193910	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-10-18	criteria provided, single submitter	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018527	SCV001244783	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-02-02	criteria provided, single submitter	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
CeGaT Center for Human Genetics Tuebingen	RCV000080373	SCV001245655	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000018527	SCV001251502	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A		criteria provided, single submitter	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000411531	SCV001370264	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2019-06-11	criteria provided, single submitter	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000018527	SCV001429469	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-07-23	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_VSTR,PS4
INGEBI, INGEBI / CONICET	RCV000211775	SCV001434024	pathogenic	Nonsyndromic genetic hearing loss	2020-08-31	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS, PS4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000080373	SCV001448121	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270107	SCV001448940	pathogenic	Hearing loss, autosomal recessive	2016-09-21	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000080373	SCV001449612	pathogenic	not provided	2015-09-03	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000080373	SCV001468968	pathogenic	not provided		criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV000146019	SCV001571776	pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PS3_Strong
Genome-Nilou Lab	RCV000018527	SCV001593117	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-03-19	criteria provided, single submitter	clinical testing	We found this variant in a patient with hearing impairment in a homozygous state.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000146019	SCV001736939	pathogenic	Hearing impairment		criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000018527	SCV001745839	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-11-08	criteria provided, single submitter	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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813994	SCV001755405	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000018527	SCV001985050	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-10-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000080373	SCV002009981	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
DASA	RCV000509532	SCV002011886	pathogenic	Deafness	2021-09-02	criteria provided, single submitter	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.
Revvity Omics, Revvity	RCV000080373	SCV002024267	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing
3billion	RCV000018527	SCV002058591	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-01-03	criteria provided, single submitter	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.
Daryl Scott Lab, Baylor College of Medicine	RCV000018527	SCV002515328	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-02-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000018527	SCV002580972	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-07-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496400	SCV002777478	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2021-10-05	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000080373	SCV002818274	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000018527	SCV003807233	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-01-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000477882	SCV003924204	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A	2021-12-10	criteria provided, single submitter	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.
UAEU Genomics Laboratory, United Arab Emirates University	RCV000018527	SCV003926558	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-03-23	criteria provided, single submitter	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000018527	SCV003932690	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-07-18	criteria provided, single submitter	clinical testing	PVS1, PM3_VS, PS4
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000018527	SCV003935282	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000080373	SCV004024406	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV003335044	SCV004046690	pathogenic	Autosomal recessive nonsyndromic hearing loss 104		criteria provided, single submitter	not provided
Genetics and Molecular Pathology, SA Pathology	RCV000018527	SCV004175439	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-05-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000080373	SCV004225747	pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	PM3_very_strong, PS4, PVS1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000018527	SCV004806830	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-03-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004562215	SCV005049709	pathogenic	GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss	2024-02-26	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000018527	SCV005397301	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-05-04	criteria provided, single submitter	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
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000018527	SCV005414380	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-11-11	criteria provided, single submitter	clinical testing
OMIM	RCV000018527	SCV000038809	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2012-10-05	no assertion criteria provided	literature only
OMIM	RCV000018528	SCV000038810	pathogenic	Deafness, digenic, GJB2/GJB6	2012-10-05	no assertion criteria provided	literature only
GeneReviews	RCV000018527	SCV000041047	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000018527	SCV000238466	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2015-03-20	no assertion criteria provided	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415175	SCV000492702	pathogenic	Severe sensorineural hearing impairment	2016-01-04	no assertion criteria provided	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477882	SCV000536698	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A	2014-10-31	no assertion criteria provided	research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018527	SCV000599723	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV001270107	SCV000607350	not provided	Hearing loss, autosomal recessive		no assertion provided	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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678860	SCV000805053	pathogenic	Hearing loss	2017-02-22	no assertion criteria provided	clinical testing
Center for Statistical Genetics, Columbia University	RCV000146019	SCV000853303	pathogenic	Hearing impairment	2018-11-22	no assertion criteria provided	research
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000018527	SCV000902318	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
University of Washington Center for Mendelian Genomics, University of Washington	RCV000146019	SCV001439097	likely pathogenic	Hearing impairment		no assertion criteria provided	research
Natera, Inc.	RCV000018527	SCV001455333	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001270107	SCV001479802	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000080373	SCV001741167	pathogenic	not provided		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542777	SCV001760317	pathogenic	Knuckle pads, deafness AND leukonychia syndrome		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000080373	SCV001972432	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000411531	SCV002011732	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2021-09-13	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000146019	SCV002106971	pathogenic	Hearing impairment	2021-01-29	no assertion criteria provided	literature only
Molecular Genetics laboratory, Necker Hospital	RCV000080373	SCV004031351	pathogenic	not provided	2019-02-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532384	SCV004114315	pathogenic	GJB2-related disorder	2024-09-10	no assertion criteria provided	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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000018527	SCV004171600	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-11-24	no assertion criteria provided	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV000018527	SCV004231802	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-06-24	no assertion criteria provided	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]
Diagnostics Centre, Carl Von Ossietzky University Oldenburg	RCV000018527	SCV005049570	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-11-08	no assertion criteria provided	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.