ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.298C>T (p.His100Tyr) (rs143343083)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000146015 SCV000193166 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Counsyl RCV000169347 SCV000220715 likely pathogenic Deafness, autosomal recessive 1A 2014-09-19 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000215444 SCV000271373 pathogenic Rare genetic deafness 2016-03-22 criteria provided, single submitter clinical testing The p.His100Tyr variant in GJB2 has been reported in >15 individuals with hearin g loss including >10 in the compound heterozygous state (Green 1999, Prasad 2000 , Pandya 2003, Feldmann 2004, Snoeckx 2005, Propst 2006, Tang 2006, Pollack 2007 , Putcha 2007, Siem 2010, Gordon 2011, Schimmenti 2011, Lipan 2011, Schimmenti 2 011). It has been identified in 3/66672 European chromosomes by the Exome Aggreg ation Consortium (ExAC,; dbSNP rs143343083). Addi tional amino acid changes at this location (p.His100Pro, p.His100Leu, and p.His1 00Gln) have been reported in individuals with hearing loss, suggesting that a ch ange at this location may not be tolerated (Gardner 2006, Snoeckx 2005, Bartsch 2010). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506227 SCV000603836 pathogenic not specified 2017-03-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169347 SCV000919427 pathogenic Deafness, autosomal recessive 1A 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.298C>T (p.His100Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Connexin, N-terminal domain (IPR013092) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study showed lack of hemichannel permeability/conductivity associated with this variant (Kim_2016). The variant was found in the control population dataset of ExAC in 5/121260 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant was reported in multiple patients with NSHL (Putcha_2007, Feldmann_2004, Lipan_2011, Burke_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000798119 SCV000937718 pathogenic not provided 2020-02-17 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 100 of the GJB2 protein (p.His100Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs143343083, ExAC 0.02%). This variant has been observed in combination with another GJB2 variant in individuals affected with deafness (PMID: 16467727, 20553101, 11102979, 21287563, 21094084, 21465647, 16222667, 17041943). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 158607). This variant has been reported to affect GJB2 protein function (PMID: 26749107). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000798119 SCV001371290 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000798119 SCV001762221 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000798119 SCV001825360 pathogenic not provided 2021-05-20 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on hemichannel permeability (Kim et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 26749107, 21465647, 16380907, 17041943, 16950989, 17666888, 11102979, 12865758, 21287563, 17935238, 25087612, 14694360, 20553101, 25388846, 31160754, 10376574)
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678877 SCV000805070 pathogenic Hearing loss 2003-02-14 no assertion criteria provided clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV001374647 SCV001571569 pathogenic nonsyndromic sensorineural hearing loss 2020-08-15 no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000798119 SCV002024269 pathogenic not provided 2019-02-27 no assertion criteria provided clinical testing

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