Total submissions: 25
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000711349 | SCV007332828 | pathogenic | not provided | 2025-01-16 | criteria provided, single submitter | clinical testing | The GJB2 c.231G>A; p.Trp77Ter variant (rs80338944, ClinVar Variation ID: 17001) is reported homozygous or compound heterozygous in the literature in multiple individuals affected with nonsyndromic hearing loss (Kelsell 1997, Salman 2015, Singh 2018). This variant is found in the South Asian population with an allele frequency of 0.11% (35/30,616 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and is predicted to result in a truncated protein. Additionally, another variant (c.230G>A, p.Trp77Ter) resulting in the same amino change has been reported in individuals with hearing loss and is considered pathogenic (Vallian 2023, Wang 2018). Based on available information, this variant is considered to be pathogenic. References: Kelsell DP et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997 May 1;387(6628):80-3. PMID: 9139825. Salman M et al. Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan. Eur Arch Otorhinolaryngol. 2015 Aug;272(8):2071-5. PMID: 25636251. Singh PK et al. Spectrum of GJB2 gene variants in Indian children with non-syndromic hearing loss. Indian J Med Res. 2018 Jun;147(6):615-618. PMID: 30168495. Vallian Broojeni J et al. Exome sequencing identifies novel variants associated with non-syndromic hearing loss in the Iranian population. PLoS One. 2023 Aug 10;18(8):e0289247. PMID: 37561809. Wang X et al. Children with GJB2 gene mutations have various audiological phenotypes. Biosci Trends. 2018 Sep 19;12(4):419-425. PMID: 30146550. |
| Otogenetics | RCV000018524 | SCV007105889 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2025-10-13 | criteria provided, single submitter | clinical testing | PVS1: Stop gain variant introduces premature stop codon in gene with loss of function as mechanism of disease, removes more than 10% of gene product; PM2: Maximum gnomAD MAF of 0.1143% in South Asian (SAS) subpopulation (<0.185% threshold); PM3_Strong: Variant reported in homozygous state in four patients and in trans with two other pathogenic variants in three patients affected with non-syndromic hearing loss (PMID: 25636251, 26061099) |
| Genetics Laboratory, |
RCV005862503 | SCV006555189 | pathogenic | Monogenic hearing loss | 2025-12-29 | criteria provided, single submitter | clinical testing | PM2_moderate, PVS1_strong, PP1_supporting, PM3_very-strong |
| Neuberg Centre For Genomic Medicine, |
RCV000018524 | SCV006311670 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | criteria provided, single submitter | clinical testing | ||
| Kasturba Medical College, |
RCV000018524 | SCV006084708 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | criteria provided, single submitter | research | A known stopgain variant c.231G>A p.(Trp77Ter) in exon 2 of GJB2 was observed in heterozygous state in proband (Saleem et al., 2021; ClinVar: VCV000017001.45). Sanger validation showed that the variant was present in heterozygous state in proband and absent in husband. This variant is present in heterozygous state in 167 individuals in the gnomAD (v4.1.0) population database, and present in three individuals in our in-house data of 3616 exomes. This variant is predicted to introduce a premature termination codon which may either lead to NMD or formation of a truncated protein product.Segregation analysis showed that the above-mentioned stop-gain variant, c.231G>A was observed in heterozygous state in proband’s mother and absent in her father | |
| Genetics and Genomic Medicine Centre, |
RCV005229816 | SCV005873780 | pathogenic | Knuckle pads, deafness AND leukonychia syndrome | 2021-10-02 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV005007866 | SCV005634674 | 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 | 2024-04-24 | criteria provided, single submitter | clinical testing | |
| Laboratory of Dr. |
RCV005420505 | SCV005627220 | pathogenic | Sensorineural hearing loss disorder | 2024-12-20 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000018524 | SCV005398796 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2022-09-02 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is 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 - The condition associated with this gene has incomplete penetrance (PMID: 31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (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 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (35 heterozygotes, 0 homozygotes). (SP) 0701 - Other protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least five pathogenic protein truncating variants downstream of this variant (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories and is a common pathogenic variant in the Pakistani population (ClinVar; PMID: 30303587). This variant has also been classified as pathogenic in the Deafness Variation Database. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| 3billion | RCV000018524 | SCV004013823 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). The variant is 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. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33187236). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33187236). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017001 / PMID: 9139825 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. | |
| Foundation for Research in Genetics and Endocrinology, |
RCV000018524 | SCV003922397 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2023-04-04 | criteria provided, single submitter | clinical testing | A heterozygous nonsense variant in exon 2 of the GJB2 gene that results in a stop codon and premature truncation of the protein at codon 77 (p.Trp77Ter) was detected. This variant has not been reported in 1000 genomes database and has a minor allele frequency of 0.004%, 0.01%, 0.0008% in the, gnomAD (v3.1), gnomdAD (v2), topmed and databases, respectively. The in silico prediction of the variant is damaging by MuttaionTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. |
| Revvity Omics, |
RCV000711349 | SCV002024261 | pathogenic | not provided | 2023-02-28 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000711349 | SCV001812639 | pathogenic | not provided | 2022-05-20 | criteria provided, single submitter | clinical testing | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22975760, 24949729, 19465004, 25087612, 25636251, 24840842, 9139825, 18941476, 29921236, 29542069, 29086887, 30168495, 20086291, 18983339, 31980526, 33614373) |
| Natera, |
RCV000018524 | SCV001453344 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2025-08-30 | criteria provided, single submitter | clinical testing | The c.231G>A variant in GJB2 is a nonsense variant predicted to introduce a stop codon at amino acid 77. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 31389194). Given the available evidence, this variant is classified as Pathogenic. |
| Baylor Genetics | RCV001004393 | SCV001163365 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B | criteria provided, single submitter | clinical testing | ||
| Labcorp Genetics |
RCV000711349 | SCV000936559 | pathogenic | not provided | 2025-11-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp77*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338944, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 9139825, 24840842, 25636251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17001). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Lys112Glufs*2) have been determined to be pathogenic (PMID: 9529365, 23141775). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000018524 | SCV000917458 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2018-06-19 | criteria provided, single submitter | clinical testing | Variant summary: GJB2 c.231G>A (p.Trp77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 246196 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00015 vs 0.025). c.231G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in homozygous and compound heterozygous state (e.g. Kelsell 1997, Santos 2005, Mani 2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV000762904 | SCV000893314 | 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 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Athena Diagnostics | RCV000711349 | SCV000841703 | pathogenic | not provided | 2023-11-30 | criteria provided, single submitter | clinical testing | This variant is expected to result in the loss of a functional protein. 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 has been identified in multiple unrelated individuals with clinical features of nonsyndromic hearing loss and deafness and is considered one of the most common causes of deafness among individuals of South Asian ancestry (PMID: 25636251). This variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic, and segregates with disease in multiple families. |
| Laboratory for Molecular Medicine, |
RCV000211767 | SCV000061488 | pathogenic | Rare genetic deafness | 2017-06-22 | criteria provided, single submitter | clinical testing | The p.Trp77X variant in GJB2 has been reported in several individuals with heari ng loss who were either homozygous or compound heterozygous with a second pathog enic variant in GJB2 (Kelsell 1997, Scott 1998, Rickard 2001, Santos 2005, Mani 2008, Padma 2009, Shafique 2014, LMM data). It has also been identified in 35/30 782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs80338944), which is consistent with the carrie r frequency for recessive hearing loss in the general population. This nonsense variant leads to a premature termination codon at position 77, which is predicte d to lead to a truncated protein. Loss of function of the GJB2 gene is an establ ished disease mechanism in autosomal recessive nonsyndromic hearing loss. In add ition, another nonsense variant at an adjacent nucleotide position (c.230G>A) re sulting in the same amino acid change has also been reported in many individuals with hearing loss (Hwa 2003, Bazazzagedan 2012, Huang 2015). Several individual s have been reported with the p.Trp77X variant; however, the nucleotide change w as not described (Cheng 2005, Bajaj 2008, Bhalla 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing l oss based upon the predicted impact of the variant, and homozygosity or compound heterozygosity in multiple affected individuals. |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000711349 | SCV001976116 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000711349 | SCV001958515 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| University of Washington Center for Mendelian Genomics, |
RCV001291332 | SCV001479806 | likely pathogenic | Hearing loss, autosomal recessive | no assertion criteria provided | research | ||
| Gene |
RCV000018524 | SCV000041041 | not provided | Autosomal recessive nonsyndromic hearing loss 1A | no classification provided | literature only | ||
| OMIM | RCV000018524 | SCV000038806 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 1997-05-01 | no assertion criteria provided | literature only |