ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.551G>A (p.Arg184Gln) (rs80338950)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000146024 SCV000193178 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000480903 SCV000568705 pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing The R184Q variant in the GJB2 gene has been reported previously as a de novo variant in individuals with hearing loss, and in a family with autosomal dominant hearing loss (Hamelmann et al., 2001; Mahdieh et al., 2010; Pang et al., 2014). The R184Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R184Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that the R184Q mutant co-localized and co-immunoprecipitated with Cx26 and Cx30, and inhibited calcein transfer (Yum et al., 2010; Zhang et al., 2011). We interpret R184Q as a pathogenic variant.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000022511 SCV000599759 pathogenic Deafness, autosomal dominant 3a 2017-05-09 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000022511 SCV000854653 pathogenic Deafness, autosomal dominant 3a 2018-12-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826191 SCV000967741 pathogenic Rare genetic deafness 2018-11-28 criteria provided, single submitter clinical testing The p.Arg184Gln variant in GJB2 has been reported in >10 individuals with hearin g loss (Amritkumar 2018, de la luz Arenas-Sordo, Hamelmann 2001, Huang 2011, Mad ieh 2010, Minarik 2012, Pang 2014, Weegerink 2011). It has been identified as a de novo variant in 5 of these individuals (Huang 2011, Madieh 2010, Pang 2014). The variant segregated in a total of 7 affected family members, with two familie s displaying autosomal dominant inheritance (Hamelmann 2001, Pavithra 2017, Weeg erink). The third family had additional GJB2 variants (Gln124X and IVS1+1G>A) th at also segregated with p.Arg184Gln in the affected family members (Pavithra 201 7, Amritkumar 2018). This variant was absent from large population studies. In v itro functional studies also suggest that this variant colocalize and coimmunopr ecipitate with wild-type Cx26 and Cx30 and inhibits dye transfer (Yum 2010, Zhan g 2011). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss. ACMG/AMP criteria applied: PS2_VeryStrong, PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001450 SCV001158696 pathogenic not specified 2019-05-28 criteria provided, single submitter clinical testing The GJB2 c.551G>A; p.Arg184Gln variant (rs80338950) is reported in the literature in multiple individuals affected with autosomal dominant nonsyndromic hearing loss (Amritkumar 2018, Hamelmann 2001, Wang 2002), including several confirmed de novo cases (Huang 2011, Pang 2014). Functional analyses of the variant protein show a dominant negative effect on both connexin 26 and connexin 30 in vitro (Su 2010, Yum 2010, Zhang 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 29662), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 184 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Amritkumar P et al. Role of DFNB1 mutations in hereditary hearing loss among assortative mating hearing impaired families from South India. BMC Med Genet. 2018 Jun 19;19(1):105. Hamelmann C Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum Mutat. 2001;18(1):84-5. Huang S et al. De novo dominant mutation of GJB2 in two Chinese families with nonsyndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2011 Oct;75(10):1333-6. 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. Su CC et al. Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30. Eur J Hum Genet. 2010 Sep;18(9):1061-4. Wang YC et al. Mutations of Cx26 gene (GJB2) for prelingual deafness in Taiwan. Eur J Hum Genet. 2002 Aug;10(8):495-8. Yum SW et al. Dominant connexin26 mutants associated with human hearing loss have trans-dominant effects on connexin30. Neurobiol Dis. 2010 May;38(2):226-36. 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.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000022511 SCV001244787 likely pathogenic Deafness, autosomal dominant 3a 2017-06-20 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_004004.5(GJB2):c.551G>A in exon 2 of the GJB2 gene.This substitution creates a minor amino acid change from an arginine to a glutamine at position 184, NP_003995.2(GJB2):p.(Arg184Gln). The argine at this position has very high conservation (100 vertebrates, UCSC). In silico tools predict this variant to be deleterious (Polyphen, SIFT, CADD, Mutation Taster).This variant is not present in the gnomAD population database. It has been previously reported as a dominant pathogenic variant in patients with nonsyndromic hearing loss (Huang. et al., (2011), Wang et al., (2002), Pang et al., (2014), Hamelmann et al., (2001)).It is not situated in a known functional domain. In addition, functional studies show that this variant causes mislocalisation of the GJB2 protien and results in a dominant negative disease mechanism (Su et al., (2010)). Based on current information, this variant has been classified as LIKELY PATHOGENIC.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000480903 SCV001450170 pathogenic not provided 2016-01-14 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000480903 SCV001480117 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
OMIM RCV000022511 SCV000043800 pathogenic Deafness, autosomal dominant 3a 2010-09-01 no assertion criteria provided literature only
GeneReviews RCV000022511 SCV000574690 pathogenic Deafness, autosomal dominant 3a 2016-12-22 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678889 SCV000805082 pathogenic Hearing loss 2014-04-07 no assertion criteria provided clinical testing

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