Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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 (http://pcpgm.partners.org /LMM). |
Counsyl | RCV000410025 | SCV000487687 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2016-08-03 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000411577 | SCV000487688 | pathogenic | Autosomal dominant nonsyndromic hearing loss 3A | 2016-08-03 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000410025 | SCV001360716 | pathogenic | Autosomal recessive nonsyndromic hearing loss 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 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 32 of the GJB2 protein (p.Arg32His). This variant is present in population databases (rs111033190, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 11493200, 15666300, 29501291). ClinVar contains an entry for this variant (Variation ID: 44766). 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: 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, 19371219, 21465647, 26346709, 27045574). 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. |
Gene |
RCV001218538 | SCV001781650 | pathogenic | not provided | 2022-01-25 | criteria provided, single submitter | clinical testing | Published functional studies suggest a damaging effect on protein localization as the mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011) and fails to form gap junction plaques (Beach et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 31162818, 25388846, 29501291, 15070423, 31589614, 20863150, 11493200, 33105617, 31160754, 27792752, 32300592) |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV000410025 | SCV004047951 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | criteria provided, single submitter | clinical testing | The GJB2 (c.95G>A) variant has been reported in multiple individuals affected with Deafness, autosomal recessive 1A (Naddafnia et. al., 2019; Roux et. al., 2004). Published functional studies suggest a damaging effect on protein localization as the mutant protein is retained in the endoplasmic reticulum (Xiao et al., 2011). The p.Arg32His variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg32His in GJB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. The amino acid Arg at position 32 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant /CNV in GJB2 gene, the molecular diagnosis is not confirmed. | |
Preventiongenetics, |
RCV003390729 | SCV004120433 | pathogenic | GJB2-related condition | 2023-07-27 | criteria provided, single submitter | clinical testing | The GJB2 c.95G>A variant is predicted to result in the amino acid substitution p.Arg32His. This variant has been reported in the homozygous and compound heterozygous states along with GJB2 premature termination variants in multiple individuals with non-syndromic hearing loss (Table 2, Marlin. 2001. PubMed ID: 11493200; Table 1, Santos. 2005. PubMed ID: 15617550; Table 2, Xia. 2016. PubMed ID: 27045574; Table 3, Gao. 2016. PubMed ID: 27792752). In vitro experimental studies suggest this variant impairs normal localization to the cell surface and may lead to premature protein degradation (Xiao. 2010. PubMed ID: 20863150; Beach. 2020. PubMed ID: 32300592). Other substitutions (Cys, Leu) at the same amino acid position have been classified as pathogenic at PreventionGenetics. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763626-C-T). This variant is interpreted as pathogenic. |
Natera, |
RCV000410025 | SCV001453358 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2020-09-16 | no assertion criteria provided | clinical testing | |
Molecular Genetics Laboratory, |
RCV001374640 | SCV001571558 | pathogenic | nonsyndromic sensorineural hearing loss | 2020-05-14 | no assertion criteria provided | clinical testing |