ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.224G>A (p.Arg75Gln) (rs28931593)

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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 RCV000211764 SCV000198162 pathogenic Rare genetic deafness 2013-08-28 criteria provided, single submitter clinical testing The Arg75Gln variant in GJB2 has been identified in several individuals with hea ring loss with or without palmoplantar keratoderma, was found to segregate with disease in over 10 affected relatives, and was determined to have occurred de no vo in at least one individual (Uyguner 2002, Feldmann 2005, Posukh 2005, Piazza 2005, Wu 2011). This variant has not been identified in large population studies . In vitro functional studies indicate the Arg75Gln variant may impact protein f unction and acts in a dominant-negative manner (Piazza 2005, Yum 2010, Zhang 201 1). In summary, this variant meets our criteria to be classified as pathogenic (
GeneDx RCV000254728 SCV000322429 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing The R75Q pathogenic variant in the GJB2 gene has been reported previously in association with autosomal dominantly-inherited progressive sensorineural hearing loss with both presence and absence of palmoplantar keratoderma (Uyguner et al., 2002; Birkenhäger et al., 2010; Jiang et al., 2014; Pavithra et al., 2015). Additionally, functional studies of the R75Q variant show that the resultant protein prevents the formation of functional channels (Piazza et al., 2005; Kim et al., 2015). The R75Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R75Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. We interpret R75Q as a pathogenic variant.
INGEBI, INGEBI / CONICET RCV001257038 SCV001433543 pathogenic Hereditary palmoplantar keratoderma; 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 c.224G>A, p.Arg75Gln variant is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This variant has been found in 6 families (2 familial cases with dominant hearing loss and palmoplantar keratoderma and 4 families with non-syndromic autosomal dominant hearing loss) and segregated it correctley in all members of the families, meeting PS4_Mod and PP1_Mod (PMID: 12372058, 15790391, 15996214, 16059934,23451214). A previous variant (p.Arg75Trp) has been previously described as causative mutation of syndromic (palmoplantar keratoderma and autosomal dominant hearing loss) and non-syndromic autosomal dominant hearing loss, applying to PM5 rule. Computational evidence predicted the mutation to be damaging to the protein (REVEL= 0.985; PP3). Functional studies in HeLa cells demonstrated that p.Arg75Gln mutant did not present dye transfer (Lucifer Yellow, Neurobiotin and calcein dyes) and showed a dominant effect when it was co-expressed with wtCX26. Besides there was a null electrical coupling (PMID: 15996214, 2104787). In addition to his, it was demonstrated a partial inhibition of neurobiotin when it was co-expressed with wtCX30 applying to PS3_Moderate rule. Therefore, the c.224G>A variant meets criteria to be classified as pathogenic for autosomal dominant non-syndromic hearing loss and syndromic hearing loss (palmoplantar keratoderma and deafness): PM2, PS4_Moderate, PP1_Moderate, PM5, PP3 and PS3_Moderate.
OMIM RCV000018554 SCV000038836 pathogenic Palmoplantar keratoderma-deafness syndrome 2005-08-30 no assertion criteria provided literature only
OMIM RCV000018555 SCV000038837 pathogenic Deafness, autosomal dominant 3a 2005-08-30 no assertion criteria provided literature only
Institut Pasteur du Maroc RCV000210858 SCV000267102 pathogenic Deafness, autosomal recessive 1A 2016-04-01 no assertion criteria provided clinical testing Pathogenic
GeneReviews RCV000018555 SCV000574686 pathogenic Deafness, autosomal dominant 3a 2016-12-22 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics, University of Washington RCV001291331 SCV001479805 likely pathogenic Deafness, autosomal recessive no assertion criteria provided research

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