ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.223C>T (p.Arg75Trp) (rs104894402)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211763 SCV000061485 pathogenic Rare genetic deafness 2014-09-29 criteria provided, single submitter clinical testing The p.Arg75Trp variant in GJB2 has been identified as the only GJB2 variant in a t least 11 individuals with hearing loss and was not identified in 120 Indian co ntrol chromosomes and 802 Chinese control chromosomes (Richard 1998, Putcha 2007 , Mani 2009, Yuan 2009, Lee 2010, Weegerink 2011, Pang 2014 and LMM unpublished data). Most reported individuals had severe to profound hearing loss that was ei ther congenital or progressive in infancy and some individuals also had palmopla ntar keratoderma. This variant occurred de novo in 3 individuals and was identif ied in three affected parents, which supports that this variant is inherited in a dominant manner (Richard 1998, Yuan 2009, Lee 2010, Weegerink 2011, Pang 2014) . This variant has not been identified in large population studies. Furthermore, Arginine at position 75 is highly conserved across species and other analogous connexin proteins (Deng, 2006). The functional assay demonstrated that the chan ge to a Tryptophan (Trp) at position 75 has a dominant negative affect on the pr otein and disrupts the function of the gap junction (Richard 1998, Maziano 2003, Deng 2006, Zhang 2011) and is important for the postnatal development of the or gan of Corti and normal hearing (Inoshita 2008, Inoshita 2014). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partner
INGEBI, INGEBI / CONICET RCV001257037 SCV001433542 pathogenic Hereditary palmoplantar keratoderma; Nonsyndromic hearing loss and deafness 2020-08-21 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.223C>T, p.Arg75Trp is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. It was found in 1/154 Egyptian controls who did not show skin disease but they had not been tested for hearing loss (PMID: 9856479) so that this evidence was not counted. The novo confirmed occurrences have been detected in two sporadic non-syndromic hearing loss cases (PMID: 11354642, 2151045) and three syndromic cases (hearing loss and palmoplantar keratoderma; PMID: 18924167, 24945352), meeting PS2_VeryStrong criteria. The p.Arg75Trp change has segregated in three different families with palmoplantar keratoderma and hearing impairment (PMID: 9856479, 20890442, 24945352) applying to PP1_Supporting rule. Besides, this variant was detected in heterozygous state in several sporadic non-syndromic hearing loss patients (PMID: 10980526, 17666888, 18941476) meeting PS4_Moderate criteria. Computational evidence predicted that the mutation has a damaging impact to the protein (REVEL=0.97; PP3). Functional studies in HeLa cells (dye transfer assays) demonstrated a dominant effect of p.Arg75Trp mutant when it was co-injected with CX26WT and CX30WT (completely inhibition of dye transfer); PMID: 12668604, 18941476. In addition to this, functional studies also showed that p.Arg75Trp mutant was incapable of inducing electrical conductance between adjacent cells and it almost completely suppressed the activity of co-expressed WT protein in Xenopus laevis oocytes (PMID: 9856479). Furthermore, transgenic mice expressing R75WCX26 mutant showed severe-profound hearing loss, deformity of supporting cells failure in the formation of the tunnel of Corti and degeneration of sensory hair cells (PMID:12700168) and it was demonstrated its importance for the postnatal development of the organ of Corti and normal hearing (PMID:18793701). Therefore, the c.223C>T variant meets criteria to be classified as pathogenic for autosomal dominant non-syndromic hearing loss and syndromic hearing loss (palmoplantar keratoderma and deafness) (PM2, PS2_VeryStrong, PS4_Moderate, PP1_Supporting, PP3 and PS3_Strong).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286491 SCV001473073 pathogenic none provided 2019-11-07 criteria provided, single submitter clinical testing The GJB2 c.223C>T; p.Arg75Trp variant (rs104894402) is reported in the literature in multiple individuals and families affected with either syndromic or nonsyndromic autosomal dominant hearing loss (ADHL), including some individuals with palmoplantar keratoderma (Lee 2010, Pang 2014, Richard 1998, Weegerink 2011, Yuan 2009). This variant is reported in ClinVar (Variation ID: 17011), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.224G>A; p.Arg75Gln) has been reported in individuals with ADHL and is considered pathogenic (Pang 2014). The arginine at codon 75 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show that arginine 75 is critical to the formation of gap junctions, and variants at this codon have dominant negative effects (Deng 2006, Marziano 2003, Richard 1998, Zhang 2011). Based on available information, the p.Arg75Trp variant is considered to be pathogenic. References: Deng Y et al. Mutations of connexin 26 at position 75 and dominant deafness: essential role of arginine for the generation of functional gap-junctional channels. Hear Res. 2006 Oct;220(1-2):87-94. Lee JY et al. Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26. J Korean Med Sci. 2010 Oct;25(10):1539-42. Marziano NK et al. Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum Mol Genet. 2003 Apr 15;12(8):805-12. Pang X et al. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans. PLoS One. 2014 Jun 19;9(6):e100483. Richard G et al. Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum Genet. 1998 Oct;103(4):393-9. Weegerink NJ Phenotypes of two Dutch DFNA3 families with mutations in GJB2. Ann Otol Rhinol Laryngol. 2011 Mar;120(3):191-7. Yuan Y et al. A de novo GJB2 (connexin 26) mutation, R75W, in a Chinese pedigree with hearing loss and palmoplantar keratoderma. Am J Med Genet A. 2009 Feb 15;149A(4):689-92. Zhang J et al. Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26. Mol Cell Neurosci. 2011 Jun;47(2):71-8.
OMIM RCV000018535 SCV000038817 pathogenic Deafness, autosomal dominant 3a 2003-05-01 no assertion criteria provided literature only
GeneReviews RCV000018535 SCV000574685 pathogenic Deafness, autosomal dominant 3a 2016-12-22 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics, University of Washington RCV001291330 SCV001479804 likely pathogenic Autosomal recessive nonsyndromic deafness no assertion criteria provided research

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