ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.427C>T (p.Arg143Trp) (rs80338948)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211779 SCV000061515 pathogenic Rare genetic deafness 2017-06-06 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 compoun d heterozygous. It has been identified in 16/23974 African chromosomes by the Ge nome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs803 38948); however, its frequency is low enough to be consistent with a recessive c arrier frequency for autosomal recessive nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessi ve hearing loss based on homozygosity and compound heterozygosity in multiple af fected individuals with hearing loss and its low frequency in the general popula tion.
Genetic Services Laboratory,University of Chicago RCV000146023 SCV000193175 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255157 SCV000227320 pathogenic not provided 2015-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000255157 SCV000322424 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing The R143W variant in the GJB2 gene has been reported previously, both in the homozygous state and in trans with a second pathogenic variant, in individuals with autosomal recessive nonsyndromic hearing loss (Brobby et al., 1998; Maheshwari et al., 2003). The R143W variant is observed in 37/276682 (0.0134%) alleles in large population cohorts (Lek et al., 2016). The R143W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies indicate that cells expressing R143W are unable to form functional channels and have altered conductance (Mese et al., 2004; Palmada et al., 2006). Missense variants in the same and nearby residues (R143Q/L, I140S, F142L, E147K) have been reported in the Human Gene Mutation Database in association with GJB2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R143W as a pathogenic variant.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000018533 SCV000599751 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515418 SCV000611272 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018533 SCV000698257 pathogenic Deafness, autosomal recessive 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 Deafness, autosomal recessive 1A 2018-03-05 criteria provided, single submitter clinical testing
Invitae RCV000255157 SCV000939977 pathogenic not provided 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 143 of the GJB2 protein (p.Arg143Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs80338948, ExAC 0.08%). This variant has been observed as homozygous or in combination with another GJB2 variant in individuals affected with hearing loss (PMID: 15365987, 19715472, 15617546, 18941476, 27792752, 23638949, 26061264). ClinVar contains an entry for this variant (Variation ID: 17009). Experimental studies have shown that this missense change causes a dominant negative effect on cell growth and reduction in cell death (PMID: 9393973, 15235031). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc 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 Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a 2019-11-14 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 Women's Health, Inc. RCV000018533 SCV001193995 pathogenic Deafness, autosomal recessive 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 Deafness, autosomal dominant 3a 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
INGEBI, INGEBI / CONICET RCV001257564 SCV001434018 pathogenic 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 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 RCV001286490 SCV001473072 pathogenic none provided 2020-06-19 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.
OMIM RCV000018533 SCV000038815 pathogenic Deafness, autosomal recessive 1A 2002-12-01 no assertion criteria provided literature only
GeneReviews RCV000018533 SCV000041048 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
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 Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control
Natera, Inc. RCV000018533 SCV001463369 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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