ClinVar Miner

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

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Total submissions: 8
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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.
Division of Genomic Diagnostics,The 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.
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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