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

gnomAD frequency: 0.00013  dbSNP: rs104894398

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211760	SCV000061478	pathogenic	Rare genetic deafness	2019-11-27	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 (Kenna 2001, Kenna 2001, Abidi 2007, Denoyelle 1997, Ben Arab 2000, Chora 2010, Dalamón 2005, Marlin 2005, Masmoudi 2000, Neocleous 2006, Pallares-Ruiz 2002, Rabionet 2000, Ravecca 2005, Samanich 2007, Toth 2004, Wang 2009, Wu 2003). It has been identified in 0.03% (13/35412) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant 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 criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago	RCV000146008	SCV000193159	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000080366	SCV000227311	pathogenic	not provided	2012-08-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000080366	SCV000491249	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 180 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: 9336442, 15070423, 32645618, 31589614, 29871260, 15964725, 30094485, 22429511, 29447821, 29625052, 30275481, 31160754, 33096615, 26553399, 21465647, 26990548, 27153395, 33105617)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018529	SCV000599733	pathogenic	Autosomal recessive nonsyndromic hearing loss 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	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	2021-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018529	SCV000698230	pathogenic	Autosomal recessive nonsyndromic hearing loss 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000080366	SCV000934792	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu47*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 180 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894398, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic hearing loss (PMID: 9336442, 15070423, 21465647, 22429511, 26553399). ClinVar contains an entry for this variant (Variation ID: 17005). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	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	RCV000080366	SCV001158600	pathogenic	not provided	2023-11-08	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 in ClinVar (Variation ID: 17005) and 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: 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. PMID: 22429511 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. PMID: 9336442 Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. PMID: 21465647 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. PMID: 10982180 Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5. PMID: 15070423
Myriad Genetics, Inc.	RCV000018529	SCV001193999	pathogenic	Autosomal recessive nonsyndromic hearing loss 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 Center for Human Genetics Tuebingen	RCV000080366	SCV001245652	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001257036	SCV001433541	pathogenic	Nonsyndromic genetic hearing loss	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 http://gnomad.broadinstitute.org; (calculated by using inverse allele frequency at ttps://www.cardiodb.org/allelefrequencyapp/), 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).
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000018529	SCV001448880	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-04-04	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV000146008	SCV001571778	pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Moderate, PM5_Moderate
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000018529	SCV001739295	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 a male patient with congenital bilateral moderate hearing loss.
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000018529	SCV003935289	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
OMIM	RCV000018529	SCV000038811	pathogenic	Autosomal recessive nonsyndromic hearing loss 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
Natera, Inc.	RCV000018529	SCV001453352	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000080366	SCV001809573	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000080366	SCV001958691	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000080366	SCV001973599	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734523	SCV005350344	pathogenic	GJB2-related disorder	2024-09-19	no assertion criteria provided	clinical testing	The GJB2 c.139G>T variant is predicted to result in premature protein termination (p.Glu47*). This variant has been reported to be causative for autosomal recessive sensorineural hearing loss (Denoyelle et al. 1997. PubMed ID: 9336442; Roux et al. 2004. PubMed ID: 15070423; Ben Said et al. 2012. PubMed ID: 22429511). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic.