ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.139G>T (p.Glu47Ter) (rs104894398)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211760 SCV000061478 pathogenic Rare genetic deafness 2011-08-19 criteria provided, single submitter clinical testing The Glu47X variant has been reported in over 20 probands with hearing loss, many of whom were homozygous or compound heterozygous with another GJB2 variant (Ken na 2001, Kenna 2001, Abidi 2007, Denoyelle 1997, Ben Arab 2000, Chora 2010, Dala mon 2005, Marlin 2005, Masmoudi 2000, Neocleous 2006, Pallares-Ruiz 2002, Rabion et 2000, Ravecca 2005, Samanich 2007, Toth 2004, Wang 2009, Wu 2003). This varia nt leads to a premature stop codon at position 47, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to b e classified as pathogenic.
Genetic Services Laboratory,University of Chicago RCV000146008 SCV000193159 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080366 SCV000227311 pathogenic not provided 2012-08-28 criteria provided, single submitter clinical testing
GeneDx RCV000080366 SCV000491249 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The E47X variant in the GJB2 gene has been reported previously in the homozygous or compound heterozygous state in numerous unrelated individuals with autosomal recessive sensorineural hearing loss and is reported to be a founder mutation in the Tunisian population (Denoyelle et al., 1997; Roux et al., 2004; Ben Said et al., 2012). This variant is predicted to cause loss of normal protein function through protein truncation. The variant is observed in 13/34402 (0.0378%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). We interpret E47X as a pathogenic variant.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018529 SCV000599733 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000080366 SCV000610238 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515308 SCV000611268 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018529 SCV000698230 pathogenic Deafness, autosomal recessive 1A 2017-06-06 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.139G>T (p.Glu47X) 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.167delT, p.Leu56fsX26; c.169C>T, p.Gln57X; c.176_191delGCTGCAAGAACGTGTG, p.Gly59fsX18; c.235delC, p.Leu79fsX3). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 23/128870 control chromosomes at a frequency of 0.0001785, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant is a common variant found in NSHL patients (homozygotes and compound heterozygotes) (Denoyelle_HMG_1997, Snoeckx_AJHG_2005, Dai_J Trans Med_2009), including one patient where it occurred as a trimutation, p.S19R/p.R32S/p.E47* (Martinez-Saucedo_IJPO_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000080366 SCV000934792 pathogenic not provided 2019-12-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Glu47*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 180 amino acids (79%) of the GJB2 protein. This variant is present in population databases (rs104894398, ExAC 0.03%). This variant has been reported in the homozygous or compound heterozgyous state in several individuals and families affected with autosomal recessive non-syndromic hearing loss (PMID: 9336442, 22429511, 15070423, 21465647, 26553399). ClinVar contains an entry for this variant (Variation ID: 17005). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000080366 SCV001143660 pathogenic not provided 2018-11-09 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. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001394 SCV001158600 pathogenic not specified 2019-06-29 criteria provided, single submitter clinical testing The GJB2 c.139G>T; p.Glu47Ter variant (rs104894398) is reported multiple times in the literature in individuals with nonsyndromic hearing loss who are homozygous for the variant or compound heterozygous with another pathogenic GJB2 variant (Ben Said 2012, Denoyelle 1997, Dodson 2011, Rabionet 2000, Roux 2004). This variant is reported as pathogenic in ClinVar (Variation ID: 17005). It is found in the general population with an overall allele frequency of 0.01% (35/282166 alleles) in the Genome Aggregation Database. 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 Link to ClinVar database for p.Glu47Ter: Ben Said M et al. Segregation of a new mutation in SLC26A4 and p.E47X mutation in GJB2 within a consanguineous Tunisian family affected with Pendred syndrome. Int J Pediatr Otorhinolaryngol. 2012 Jun;76(6):832-6. Denoyelle F et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997 Nov;6(12):2173-7. Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4. Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5.
Myriad Women's Health, Inc. RCV000018529 SCV001193999 pathogenic Deafness, autosomal recessive 1A 2019-12-26 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.139G>T(E47*) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 21465647 and 17041943. Classification of NM_004004.5(GJB2):c.139G>T(E47*) 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000080366 SCV001245652 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
INGEBI, INGEBI / CONICET RCV001257036 SCV001433541 pathogenic Nonsyndromic hearing loss and deafness 2020-08-21 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.139 G>T (p.Glu47*) variant in the GJB2 gene is 0.02% (13/35412) of Latino chromosomes by the Genome Aggregation Database; (calculated by using inverse allele frequency at ttps://, which meets the PM2_Supporting rule. The p.Glu47* variant 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 of disease (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID: 9336442, 10905664, 12910486, 14985372, 24158611). The c.139G>T variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: (PVS1, PM2_Supporting, PM3_VeryStrong).
OMIM RCV000018529 SCV000038811 pathogenic Deafness, autosomal recessive 1A 1998-05-28 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678867 SCV000805060 pathogenic Hearing loss 2017-01-10 no assertion criteria provided clinical testing

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