ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.95G>A (p.Arg32His) (rs111033190)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037873 SCV000061535 pathogenic Rare genetic deafness 2014-06-30 criteria provided, single submitter clinical testing The Arg32His variant in GJB2 has been reported in many probands with sensorineur al hearing loss (Wajid 2004, Chaleshtori 2005, Pollak 2007, Bonyadi 2009, Feldm ann 2004, Hamid 2009, Marlin 2005, Marlin 2001, Mustapha 2001, Najmabadi 2005, P utcha 2007, Roux 2004, Santos 2005, Siemering 2006, Snoeckx 2005). At least 15 o f these probands were homozygous or compound heterozygous. In summary, this vari ant meets our criteria to be classified as pathogenic ( /LMM).
Counsyl RCV000410025 SCV000487687 pathogenic Deafness, autosomal recessive 1A 2016-08-03 criteria provided, single submitter clinical testing
Counsyl RCV000411577 SCV000487688 pathogenic Deafness, autosomal dominant 3a 2016-08-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410025 SCV001360716 pathogenic Deafness, autosomal recessive 1A 2019-11-08 criteria provided, single submitter clinical testing Variant summary: GJB2 c.95G>A (p.Arg32His) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250526 control chromosomes (gnomAD). c.95G>A has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Baux_2017, Marlin_2001, Mustapha_2001, Snoeckx_2005). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects gap junction functions by causing impaired membrane targeting and aberrant cellular localization (Xiao_2011). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001218538 SCV001390424 pathogenic not provided 2019-06-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 32 of the GJB2 protein (p.Arg32His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs111033190, ExAC 0.001%). This variant has been observed in individuals affected with autosomal recessive non-syndromic hearing loss (PMID: 11493200, 29501291, 15666300). ClinVar contains an entry for this variant (Variation ID: 44766). This variant has been reported to affect GJB2 protein function (PMID: 20863150). This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11102979, 27045574, 21465647, 19371219, 26346709). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001218538 SCV001781650 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing Observed in unrelated patients with hearing loss in published literature (Marlin et al., 2001; Roux et al., 2004); Published functional studies suggest a damaging effect on protein localization; mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 33105617, 31589614, 31160754, 32300592, 11493200, 15070423, 29501291, 25388846, 27792752, 20863150, 31162818)
Natera, Inc. RCV000410025 SCV001453358 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV001374640 SCV001571558 pathogenic nonsyndromic sensorineural hearing loss 2020-05-14 no assertion criteria provided clinical testing

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