ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.132G>A (p.Trp44Ter) (rs104894407)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146007 SCV000193158 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000593364 SCV000700809 pathogenic not provided 2016-12-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000593364 SCV000883945 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing The GJB2 c.132G>A; p.Trp44Ter variant (rs104894407) has been reported in the literature in individuals with hearing loss who carried a pathogenic variant on the opposite chromosome (Green 1999, Martinez-Saucedo 2015, Roux 2004). It is reported in ClinVar (Variation ID: 158605), and observed in the general population databases at a frequency of 0.003 percent (8/276604 alleles; Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp44Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/158605/ Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Martinez-Saucedo M et al. Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2015 Dec;79(12):2295-9. Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5.
Invitae RCV000593364 SCV000933879 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Trp44*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acids of the GJB2 protein. This variant is present in population databases (rs104894407, ExAC 0.06%). This variant has been observed in many individuals affected with non-syndromic hearing loss and to segregate with non-syndromic hearing loss in families (PMID: 26553399, 26346709, 15070423, 10376574). ClinVar contains an entry for this variant (Variation ID: 158605). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000593364 SCV001168433 pathogenic not provided 2021-04-19 criteria provided, single submitter clinical testing Observed with a pathogenic variant in additional unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17666888, 15070423, 26553399, 18758381, 10376574, 31589614)
Counsyl RCV000984267 SCV001132398 likely pathogenic Deafness, autosomal recessive 1A 2015-03-06 no assertion criteria provided clinical testing
Natera, Inc. RCV000984267 SCV001453353 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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