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

gnomAD frequency: 0.00001  dbSNP: rs72561723

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851914	SCV002241910	pathogenic	not provided	2024-06-29	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)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018561	SCV005397988	pathogenic	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0254 - This variant is confirmed mosaic. (I) 0304 - Variant is present in gnomAD v3 <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0801 - This variant has been inherited as well as detected germline mosaic in individuals with autosomal dominant keratitis-ichthyosis-deafness syndrome in the absence of p.(Tyr136*). This variant and nonsense variant p.(Tyr136*) in cis are reported to be associated with autosomal recessive deafness. Additionally this variant has been identified somatic mosaic in individuals with porokeratotic eccrine ostial and dermal duct nevus (PEODDN) and nevoid spiny hyperkeratosis (ClinVar, Deafness Variation db, PMID:25692760, PMID:32120898, PMID:27087580, PMID:24785414, PMID:20412116). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies showed cells co-transfected with this variant and wild type, failed to form gap junctions, demonstrated aberrant gating activity, and resulted in cell death (PMID:27761313, PMID:24785414). Additionally, mutagenesis studies showed this variant, when in cis with the nonsense p.(Tyr136*) variant, frequently seen in the Japanese population, cancels the dominant lethal effects of p.(Gly45Glu), causing autosomal recessive non-syndromic deafness (PMID:32120898, PMID 24785414, PMID: 27761313). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005007870	SCV005634682	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A	2024-04-20	criteria provided, single submitter	clinical testing
OMIM	RCV000018561	SCV000038843	pathogenic	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome	2011-12-01	no assertion criteria provided	literature only