Submissions for variant NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)

gnomAD frequency: 0.00021  dbSNP: rs80338948

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211779	SCV000061515	pathogenic	Rare genetic deafness	2019-05-14	criteria provided, single submitter	clinical testing	The p.Arg143Trp variant in GJB2 has been reported in many probands with hearing loss (Brobby 1998, Abe 2000, Rabionet 2000, Kenna 2001, Cryns 2004, Chaleshtori 2005, Snoeckx 2005, LMM data). Most of these probands were homozygous or compound heterozygous. It has also been identified in 0.07% (18/24908) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency for autosomal recessive nonsyndromic hearing loss. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies support an impact on protein function (Meşe 2004, Palmada 2006). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Supporting, PP3.
Genetic Services Laboratory, University of Chicago	RCV000146023	SCV000193175	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000255157	SCV000227320	pathogenic	not provided	2015-05-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000255157	SCV000322424	pathogenic	not provided	2024-07-05	criteria provided, single submitter	clinical testing	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: 16300957, 25388846, 30455902, 34943631, 25087612, 12833397, 21465647, 25266519, 15241677, 12562518, 19043807, 31370293, 31162818, 30146550, 32012697, 9393973, 15235031, 31541171, 31160754, 30275481, 32645618, 33597575, 33096615, 31589614, 29871260, 33297549, 32067424, 36147510, 34599368, 35114279, 35939872, 37108562, 35336849, 36493725, 35982127, 9471561, 38069086, 34519870, 37561809, 36048236, 35853923)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018533	SCV000599751	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515418	SCV000611272	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; X-linked mixed hearing loss with perilymphatic gusher	2021-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018533	SCV000698257	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-04-21	criteria provided, single submitter	clinical testing	Variant summary: The c.427C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Arg to Trp. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 20/121442 control chromosomes at a frequency of 0.0001647, which does not exceed maximal expected frequency of a pathogenic allele (0.025). The variant of interest has been reported to be a common pathogenic variant predominantly found in Ghana (Hamelmann_2001). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000018533	SCV000784259	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-03-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255157	SCV000939977	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the GJB2 protein (p.Arg143Trp). This variant is present in population databases (rs80338948, gnomAD 0.07%). This missense change has been observed in individuals with hearing loss (PMID: 15365987, 15617546, 18941476, 19715472, 23638949, 26061264, 27792752). ClinVar contains an entry for this variant (Variation ID: 17009). 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: 9393973, 15235031). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000255157	SCV001143669	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027826	SCV001190446	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	2021-12-10	criteria provided, single submitter	clinical testing	GJB2 NM_004004.5 exon 2 p.Arg143Trp (c.427C>T): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with nonsyndromic hearing loss, segregating with disease in multiple affected family members (Brobby 1998 PMID:9471561, Abe 2000 PMID:10633133, Maheshwari 2003 PMID:12833397, Cryns 2004 PMID:14985372, Kenna 2010 PMID:20083784, Dodson 2011 PMID:21465647, Abe 2018 PMID:30455902). This variant is present in 0.07% (18/24908) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-20763294-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17009). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies have shown that this mutant protein is unable to from functional channels (Palmada 2006 PMID:16300957). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above (segregation studies, impact to protein etc.).
Myriad Genetics, Inc.	RCV000018533	SCV001193995	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-24	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.427C>T(R143W) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 11439000, 12562518, 15241677 and 16300957. Classification of NM_004004.5(GJB2):c.427C>T(R143W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196233	SCV001366784	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
INGEBI, INGEBI / CONICET	RCV001257564	SCV001434018	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.427C>T, p.Arg143Trp variant in GBJ2 gene is 0,04% (18/24908 African chromosomes with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria. The p.Arg143Trp change was identified in trans with at least 7 known pathogenic variants applying to PM3_VeryStrong rule(PMID: 9471561, 14985372, 10633133, 11556849, 10982180, 24158611). In one family this variant was identified in trans with a reported pathogenic variant and segregated among family members applying to PP1_Supporting criteria (PMID: 10633133). Computational analysis predicted a pathogenic impact of the mutation to the protein (REVEL=0.918; PP3). Functional studies demonstrated that p.Arg143Trp mutant formed functional channels that were permeable to fluorescent tracers in transfected N2A cells and conductance levels measured similar to that of WT-Cx26 (PMID: 12562518). However, it did not induce the formation of functional GJCh in paired Xenopus laevis oocytes (PMID: 15241677, 16300957). As the evidence is contradictory functional data was not counted. In summary, This variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PM3_VeryStrong, PP1_Supporting and PP3.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255157	SCV001473072	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	The GJB2 c.427C>T; p.Arg143Trp variant (rs80338948) is a well-studied pathogenic variant associated with autosomal recessive deafness-1A (DFNB1A) and has been observed in affected individuals both in the homozygous state and in trans to other pathogenic GJB2 variants (Abe 2018, Brobby 1998, Dodson 2011, Sloan-Heggen 2016). This variant is found in the African population with an overall allele frequency of 0.07% (18/24908 alleles) in the Genome Aggregation Database, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17009). The arginine at codon 143 is highly conserved, and while conclusions from functional studies are somewhat varied, functional assays indicate that the p.Arg143Trp variant inhibits gap junction formation and reduced conductance (Wang 2003, Mese 2004, Palmada 2006). Additionally, other amino acid substitutions at this codon (p.Arg143Gln, p.Arg143Leu) have been reported in individuals with hearing loss and are considered disease-causing (Loffler 2001, Putcha 2007). Based on available information, the p.Arg143Trp variant is considered to be pathogenic. References: Abe S et al. Diagnostic pitfalls for GJB2-related hearing loss: A novel deletion detected by Array-CGH analysis in a Japanese patient with congenital profound hearing loss. Clin Case Rep. 2018 Sep 21;6(11):2111-2116. Brobby et al. Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa. N Engl J Med. 1998; 338(8): 548-550. Dodson et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011; 155A(5): 993-1000. Loffler J et al. Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. Eur J Hum Genet. 2001 Mar;9(3):226-30. Mese et al. Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum Genet. 2004; 115(3): 191-199. Palmada et al. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006; 22(1): 112-118. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016; 135(4): 441-450. Wang et al. Functional analysis of connexin-26 mutants associated with hereditary recessive deafness. J Neurochem. 2003; 84(4): 735-742.
Revvity Omics, Revvity	RCV000255157	SCV002024270	pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018533	SCV005399350	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (67 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 6 heterozygotes, 0 homozygotes). (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 very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported pathogenic in >10 unrelated individuals with hearing loss (ClinVar, Deafness Variation database). This variant has also been reported compound heterozygous with other well-known pathogenic variants in individuals with hearing loss and homozygous in an individual with profound non-syndromic hearing loss (PMID:38730444). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000018533	SCV005416499	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A		criteria provided, single submitter	clinical testing	PS3_Moderate+PM3_VeryStrong+PM5
OMIM	RCV000018533	SCV000038815	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2002-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000018533	SCV000041048	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678885	SCV000805078	pathogenic	Hearing loss	2014-10-02	no assertion criteria provided	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000018533	SCV000902311	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000018533	SCV001463369	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255157	SCV001956935	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255157	SCV001964498	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532385	SCV004116141	pathogenic	GJB2-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The GJB2 c.427C>T variant is predicted to result in the amino acid substitution p.Arg143Trp. This variant was reported in an individual with autosomal recessive nonsyndromic hearing loss (Brobby et al 1998. PubMed ID: 9471561; Maheshwari et al. 2003. PubMed ID: 12833397; Abe et al. 2018. PubMed ID: 30455902). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.