ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)

gnomAD frequency: 0.00002  dbSNP: rs104894396
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 38
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000211778 SCV000840546 pathogenic Nonsyndromic genetic hearing loss 2018-09-17 reviewed by expert panel curation The filtering allele frequency of the p.Trp24X variant in the GJB2 gene is 0.38% (137/ 30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1 code will not contribute to the overall classification. The p.Trp24X variant in GJB2 is predicted to cause a premature stop codon in the only exon of GJB2 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: 15070423, 24123366, 18941476, 9139825). A knock-in mouse model demonstrates that the p.Trp24X variant leads to the phenotype (PS3; PMID:18941476). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS3, BS1.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000844631 SCV000061533 pathogenic Rare genetic deafness 2008-02-25 criteria provided, single submitter clinical testing The Trp24X variant in GJB2 is a known pathogenic variant and has been reported i n many individuals affected with hearing loss (Kelsell 1997, Roux 2004, Mani 200 9). ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory,University of Chicago RCV000146028 SCV000193182 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000255370 SCV000322098 pathogenic not provided 2020-04-27 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation, as the last 203 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014) Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840546.3; Oza et al., 2018) This variant is associated with the following publications: (PMID: 31160754, 32847582, 31980526, 31827275, 33111345, 26689913, 18294064, 18941476, 29907799, 30394532, 30168495, 29086887, 29542069, 30094485, 15113126, 14985372, 11968091, 12746422, 16380907, 25636251, 26850479, 26778469, 26059209, 25999548, 9139825, 24840842, 24123366, 22975760, 15070423, 16088916, 12833397)
Eurofins NTD LLC (GA) RCV000255370 SCV000330928 pathogenic not provided 2016-07-19 criteria provided, single submitter clinical testing
Counsyl RCV000411010 SCV000487396 pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2015-12-18 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000018525 SCV000493065 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2016-12-08 criteria provided, single submitter research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000018525 SCV000599727 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515359 SCV000611274 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 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000018525 SCV000698272 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2016-06-28 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.71G>A (p.Trp24X) 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. Functional analysis showed that this results into truncated protein; the mutant protein does not undergo nonsense mediated decay (Mani_2009). Thus it causes loss of connexin and gap junction channel protein cysteine-rich domains. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.Trp44X, p.Gln124X, etc.). This variant was found in 70/121380 control chromosomes at a frequency of 0.0005767, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). In literature, this variant is reported as one of the common pathogenic variants, found especially in India, with consistent clinical (cosegregation and genotypic) data supporting for pathogenicity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Athena Diagnostics Inc RCV000255370 SCV000841712 pathogenic not provided 2019-04-23 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255370 SCV000883943 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing The GJB2 c.71G>A; p.Trp24Ter variant (rs104894396) is a common pathogenic variant reported in association with autosomal recessive hearing loss. In a large multi-center North American cohort it accounted for 1.41% of pathogenic variants identified in GJB2 (33 out of 2,341 variants) (Putcha 2007). This variant is also reported in ClinVar (Variation ID: 17002). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Putcha 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.
Illumina Laboratory Services,Illumina RCV000018525 SCV000915627 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-04-27 criteria provided, single submitter clinical testing The GJB2 c.71G>A (p.Trp24Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp24Ter variant has been identified in at least 46 patients with a recessive form of nonsyndromic hearing loss including in 28 in a homozygous state, 12 in a compound heterozygous state, and 6 in a heterozygous state (Kelsell et al. 1997; Maheshwari et al. 2003; RamShankar et al. 2003; Alvarez et al. 2005; Salman et al. 2015). The variant has been shown to segregate with disease in an autosomal recessive pattern in affected families (Maheshwari et al. 2003). The p.Trp24Ter variant was reported in five of 285 controls in a heterozygous state, which is consistent with carrier frequency, and is reported at a frequency of 0.00399 in the South Asian population of the Exome Aggregation Consortium. RamShankar et al. (2003) found that the p.Trp24Ter variant was the most common variant among 215 Indian probands and suggested a founder effect was responsible for the estimated carrier frequency of 0.024 in the Indian population. The variant has not been reported in association with Vohwinkel syndrome, ichthyosis hystrix-like with deafness, keratitis-ichthyosis-deafness syndrome or the dominant form of nonsyndromic hearing loss, all conditions known to be caused by variants in the GJB2 gene. Based on the disease prevalence and frequency of the variant, the p.Trp24Ter variant can be ruled out of causing disease in these conditions despite the potential impact of stop-gained variants. However, based on the collective evidence, the p.Trp24Ter variant is classified as pathogenic for the recessive form of 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 RCV000018525 SCV000928357 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2018-05-20 criteria provided, single submitter clinical testing PS3, PM1, PM4, PP2, PP3
Invitae RCV000255370 SCV000946811 pathogenic not provided 2021-12-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp24*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 203 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894396, gnomAD 0.4%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness in several families and to be a common cause of the disease in many populations (PMID: 12833397, 15146474, 16088916, 24840842, 26059209). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17002). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GJB2 function (PMID: 18941476). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004398 SCV001163370 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000018525 SCV001193811 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2019-11-12 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.71G>A(W24*) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 15070423, 19371219, 15967879, 18941476 and 22695344. Classification of NM_004004.5(GJB2):c.71G>A(W24*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000018525 SCV001244788 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-12-28 criteria provided, single submitter clinical testing A homozygous nonsense variant, NM_004004.5(GJB2):c.71G>A, has been identified in exon 2 of 2 of the GJB2 gene. The variant is predicted to result in a premature stop codon at position 24 of the protein (NP_003995.2(GJB2):p.(Trp24*)). Functional studies show that this variant is predicted to affect gap junction acitivty and create a defective cellular localization (Mani et al. 2009). The variant is present in the gnomAD database at a frequency of 0.0005% . This variant has been previously described as pathogenic in association with autosomal recessive deafness (ClinVar, Toth et al., (2004)). This variant has also been shown to segregate with the disease in at least 3 families (Rehmen et al., 2014). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
CeGaT Center for Human Genetics Tuebingen RCV000255370 SCV001245654 pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001112641 SCV001270323 likely benign Ichthyosis, hystrix-like, with hearing loss 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services,Illumina RCV000411010 SCV001270324 likely benign Autosomal dominant nonsyndromic hearing loss 3A 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000411010 SCV001367896 pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PM4,PP3,PS1,PP4.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV000146028 SCV001571774 pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PVS1_Strong, PS3_Moderate, PM2_Moderate, PP1_Supporting
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000018525 SCV001870364 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2021-04-12 criteria provided, single submitter research ACMG codes:PVS1, PM2, PP5
Breda Genetics srl RCV000018525 SCV001977005 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2021-06-29 criteria provided, single submitter clinical testing The variant c.71G>A (p.Trp24*) in the GJB2 gene is reported as a pathogenic for GJB2-related autosomal recessive deafness in ClinVar (Variation ID: 17002). This mutation has been described in multiple papers and is considered common in the Pakistani and Indian population (Richard et al., 2019, PMID: 30303587; Shaik et al., 2017, PMID: 29086887; Santos et al., 2005, PMID: 15617550). It creates a premature stop codon at amino acid position Trp24, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allelic frequency of 0.0006 in gnomAD exomes and 0.0000319 in gnomAD genomes, with one homozygous individual reported.
Mendelics RCV002247354 SCV002516479 pathogenic Mutilating keratoderma 2022-05-04 criteria provided, single submitter clinical testing
3billion RCV000018525 SCV002521310 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2022-05-22 criteria provided, single submitter clinical testing The substitution creates a nonsense variant within 50 bp downstream of the penultimate exon or last exon. While it is expected to escape nonsense-mediated decay, the truncated region is considered critical. Functional assays showed that the variant had strong level of impact on gene/protein function (PMID: 18941476).This variant has been reported as pathogenic multiple times (ClinVar ID: VCV000017002,PMID:9139825, 3billion database) and observed to be in trans with another pathogenic variant in this gene (PMID: 15070423, 18941476, 24123366, 9139825). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000018525 SCV000038807 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2005-09-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000018525 SCV000238404 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2014-06-23 no assertion criteria provided research The variant (c. 71G>A, p. W24*) has been previously associated with autosomal recessive hearing loss (Kelsell et al. 1997, PMID: 9139825; Maheshwari et al. 2003, PMID: 12833397; Minarik et al. 2003, PMID: 15113126; Roux et al. 2004, PMID: 15070423; Toth et al. 2004, PMID: 15146474; Alvarez et al. 2005, PMID: 16088916; Bouwer et al. 2007, PMID: 18294064). This variant has been described as the most common GJB2 variant in individuals of Indian descent (2.4% carrier frequency) and Roma descent (4-5% carrier frequency) (Bouwer et al. 2007, PMID: 18294064). This variant is a nonsense variant predicted to create a premature stop codon. Functional analysis suggests that this variant affects the gap junction activity (Mani et al. 2009, PMID: 18941476). Taken together this variant is considered a pathogenic variant.
Kasturba Medical College, Manipal, Manipal Academy of Higher Education RCV000018525 SCV000777827 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2018-05-15 no assertion criteria provided research
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678864 SCV000805057 pathogenic Hearing loss 2014-10-27 no assertion criteria provided clinical testing
Center for Statistical Genetics, Columbia University RCV000146028 SCV000853304 pathogenic Hearing impairment 2018-11-22 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000146028 SCV001439098 likely pathogenic Hearing impairment no assertion criteria provided research
Natera, Inc. RCV000018525 SCV001455332 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 RCV001291329 SCV001479803 likely pathogenic Hearing loss, autosomal recessive no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255370 SCV001952327 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000255370 SCV001971394 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000255370 SCV002024258 pathogenic not provided 2021-09-02 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.