ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.71G>A (p.Trp24Ter) (rs104894396)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255370 SCV000883943 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255370 SCV000841712 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing
Center for Statistical Genetics, Columbia University RCV000146028 SCV000853304 pathogenic Hearing impairment 2018-11-22 no assertion criteria provided research
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000211778 SCV000840546 pathogenic Nonsyndromic hearing loss and deafness 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678864 SCV000805057 pathogenic Hearing loss 2014-10-27 no assertion criteria provided clinical testing
Counsyl RCV000018525 SCV000487395 pathogenic Deafness, autosomal recessive 1A 2015-12-18 criteria provided, single submitter clinical testing
Counsyl RCV000411010 SCV000487396 pathogenic Deafness, autosomal dominant 3a 2015-12-18 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018525 SCV000599727 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000018525 SCV000238404 pathogenic Deafness, autosomal recessive 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255370 SCV000330928 pathogenic not provided 2016-07-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515359 SCV000611274 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000255370 SCV000322098 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing The W24X variant in the GJB2 gene has been reported previously in the homozygous or compound heterozygous state in multiple individuals with moderate to profound hearing loss and is one of the most common pathogenic GJB2 variants reported among South Asian individuals (Kelsell et al., 1997; Mani et al., 2009; Pavithra et al., 2014; Salman et al., 2015; Mahdieh et al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. Although not present in the homozygous state in any control individuals, the W24X variant is observed in 66/16,512 alleles (0.4%) from individuals of South Asian background in the ExAC dataset, consistent with the high prevalence of W24X as a pathogenic GJB2 variant within this population (Lek et al., 2016; Mahdieh et al., 2016). We interpret W24X as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000146028 SCV000193182 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000018525 SCV000493065 pathogenic Deafness, autosomal recessive 1A 2016-12-08 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000018525 SCV000915627 pathogenic Deafness, autosomal recessive 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.
Integrated Genetics/Laboratory Corporation of America RCV000018525 SCV000698272 pathogenic Deafness, autosomal recessive 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.
Invitae RCV000255370 SCV000946811 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Trp24*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 203 amino acids of the GJB2 protein. This variant is present in population databases (rs104894396, ExAC 0.4%). This variant has been observed to segregate with hearing loss in several families and to be a common cause of the disease in many populations (PMID: 12833397, 16088916, 24840842, 15146474, 26059209). ClinVar contains an entry for this variant (Variation ID: 17002). Experimental studies have shown that this nonsense change expresses full-length protein but disrupts cellular localization in vitro (PMID: 18941476). For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College,Manipal University RCV000018525 SCV000777827 pathogenic Deafness, autosomal recessive 1A 2018-05-15 no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare 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.
Laboratory of Medical Genetics,National & Kapodistrian University of Athens RCV000018525 SCV000928357 pathogenic Deafness, autosomal recessive 1A 2018-05-20 criteria provided, single submitter clinical testing PS3, PM1, PM4, PP2, PP3
OMIM RCV000018525 SCV000038807 pathogenic Deafness, autosomal recessive 1A 2005-09-01 no assertion criteria provided literature only

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