ClinVar Miner

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

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Total submissions: 12
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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
Counsyl RCV000018529 SCV000220468 pathogenic Deafness, autosomal recessive 1A 2014-07-01 criteria provided, single submitter literature only
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; 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
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 2018-12-26 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.
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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