ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.134G>A (p.Gly45Glu)

gnomAD frequency: 0.00001  dbSNP: rs72561723
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000022510 SCV000220956 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2014-12-13 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022510 SCV001360714 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2019-08-21 criteria provided, single submitter clinical testing Variant summary: GJB2 c.134G>A (p.Gly45Glu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092)/first extracellular loop domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250912 control chromosomes. c.134G>A has been reported as a de-novo variant or as a somatic mosaic in the literature in multiple individuals affected with Keratitis Ichthyosis Deafness Syndrome (KID) (Janecke_2005, Griffith_2006, Jonard_2008, Sbidian_2010, Ogawa_2014, Eskin-Schwartz_2016). These data indicate that the variant is very likely to be associated with disease. Co-occurrence in cis with another pathogenic variant have been reported in the Japanese population (GJB2 c.408C>A, p.Tyr436*), providing supporting evidence for a benign role in the setting of Autosomal Recessive Non-syndromic deafness (Fuse_1999, Ogawa_2014). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete inability to form functional gap junctions (Rodriguez-Paris_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant when observed in isolation was classified as pathogenic for a phenotype of KID.
Invitae RCV001851914 SCV002241910 pathogenic not provided 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 45 of the GJB2 protein (p.Gly45Glu). This variant is present in population databases (rs72561723, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal dominant keratitis-ichthyosis-deafness syndrome, in the absence of p.Tyr136* (PMID: 15633193, 16885744, 18024254, 24785414). In at least one individual the variant was observed to be de novo. Therefore, when present alone (i.e. without a loss of function variant in cis that causes nonsense-mediated decay of the transcript), this variant is expected to be causative for autosomal dominant keratitis-ichthyosis-deafness syndrome. This variant has also been reported in combination with p.Tyr136* in individuals with autosomal recessive non-syndromic deafness (PMID: 10501520, 26763877); the p.[Tyr136*;Gly45Gly] haplotype is expected to be causative for autosomal recessive non-syndromic deafness. ClinVar contains an entry for this variant (Variation ID: 17033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 17428836, 22031297, 24785414, 27761313). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001851914 SCV002499796 pathogenic not provided 2022-03-25 criteria provided, single submitter clinical testing Published functional studies demonstrate a dominant negative effect on hemichannel function, resulting in increased cell death (Gerido et al., 2007; Mese et al., 2008); Published functional studies demonstrate that the dominant negative effect of p.(G45E) on gap junction formation is neutralized by the presence of p.(Y136*) on the same allele (in cis), and that the complex allele results instead in a loss of protein function (Rodriguez-Paris 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: 24359977, 27087580, 16950989, 21292415, 20584891, 30287322, 12560944, 23756814, 19043807, 26763877, 25388846, 31160754, 10633133, 31331740, 17146396, 17428836, 22031297, 10501520, 15633193, 24785414, 16885744, 18024254, 27761313, 20412116)
OMIM RCV000018561 SCV000038843 pathogenic Autosomal dominant keratitis-ichthyosis-hearing loss syndrome 2011-12-01 no assertion criteria provided literature only

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