ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.478G>A (p.Gly160Ser) (rs34988750)

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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 RCV000037858 SCV000061520 benign not specified 2010-12-17 criteria provided, single submitter clinical testing Gly160Ser in exon 2 of GJB2: This variant has been identified at a frequency of 0.1-0.5% in several studies of individuals with hearing loss (Janecke 2002, Bati ssoco 2008, Gasmelseed 2004, Ross 2007). However, in none of these individuals w as a second GJB2 variant identified. In addition, this variant has been identifi ed in 3/140 (2%) controls (Scott 1998, rs34988750). In summary, the Gly160Ser va riant is not expected to have clinical or pathological significance due to its o ccurrence at a lower frequency in cases compared to controls.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000037858 SCV000112275 benign not specified 2012-12-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000037858 SCV000193177 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000304812 SCV000382997 likely benign Keratitis-Ichthyosis-Deafness Syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000359564 SCV000382998 likely benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000264732 SCV000382999 likely benign Mutilating keratoderma 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000329133 SCV000383000 likely benign Hystrix-like ichthyosis with deafness 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000365268 SCV000383001 likely benign Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000501921 SCV000590938 uncertain significance Nonsyndromic Deafness 2017-05-19 criteria provided, single submitter clinical testing Reported in gene specific databases (davinci.crg.es/deafness/index.php), ClinVar, and the scientific literature as benign. The evidence for this classification is unclear/not provided, but at least in some cases appears to be due to a reported control population allele frequency of 2% (Scott et al., 1998 PMID: 9600457). This variant is reported in population databases at frequencies of up to 0.22% (gnomAD, ExAC). In silico analyses predict an impact on the protein.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037858 SCV000603823 uncertain significance not specified 2016-09-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587337 SCV000698260 likely benign not provided 2017-02-10 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.478G>A (p.Gly160Ser) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 68/129050 control chromosomes at a frequency of 0.0005269, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in hearing loss patients without strong evidence for pathogenicity. In a dominant hearing loss family, the variant did not co-segregate with the disease, suggesting an alternate molecular mechanism for the disease (Janecke_2002). Moreover, the dominant inheritance of this variant can be ruled out because of higher prevalence in controls (1:1897), than the prevalence of ADNSHL due to GJB2 (1:40,000). An evidence supporting the benign nature of this variant comes from the Putcha_2007 study, which identified the variant in 7:7401 North American hearing loss patients. This represents an allele frequency of 1:2114 in the North American hearing loss population, while the allele frequency of the variant in the ESP control cohort is 1:1300 and the combined allele frequency for diverse ethnicities in ExAC is 1:1891. This indicates the benign nature of the variant. The variant has been commonly reported in hearing loss patients in heterozygous state, not indicating for a pathogenic outcome. In two autosomal recessive NSHL patients, this variant was found to be in cis with a known pathogenic variant c.235delC (Zheng_2015), strongly supporting for a benign outcome of this variant. Furthermore, multiple clinical laboratories via ClinVar classify variant as Benign/likely benign (without evidence to independently evaluate). Considering all pieces of evidence, the variant is classified as likely benign.
Counsyl RCV000674006 SCV000799275 uncertain significance Deafness, autosomal recessive 1A 2018-04-09 criteria provided, single submitter clinical testing

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