ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.563A>G (p.Lys188Arg) (rs1131691709)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004776 SCV001164258 likely pathogenic Nonsyndromic hearing loss and deafness 2019-10-31 reviewed by expert panel curation The allele frequency of the c.563A>G (p.Lys188Arg) variant in GJB2 is 0.006% (1/15428) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). This variant has been detected in four probands patients with hearing loss (PMID 17666888, University of Minnesota internal data, GeneDx internal data). For two of those probands, a pathogenic was observed in trans, and in one individual a second pathogenic variant was observed but phase was not determined (PM3_Strong; PMID 17666888, University of Minnesota internal data, GeneDx internal data). The REVEL computational prediction analysis tool produced a score of 0.9, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3_Strong, PP3).
GeneDx RCV000493772 SCV000582691 pathogenic not provided 2017-04-24 criteria provided, single submitter clinical testing The K188R variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic sensorineural hearing loss (Putcha et al., 2007). The K188R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K188R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (R184G, R184W, R184Q, R184P, T186M, T186K, V190D) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret K188R as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000493772 SCV000698268 uncertain significance not provided 2016-04-21 criteria provided, single submitter clinical testing Variant summary: The c.563A>G variant involves the alteration of one of 5 invariant amino acid residues in the Connexin domain of GJB2 and 4/5 in silico tools predict a pathogenic outcome. The variant is absent from the large, broad ExAC control population and has been reported in the literature in two patients with hearing loss, at least one of whom also carried the known pathogenic GJB2 c.35delG variant in trans (Putcha_2007). Additionally, When expressed in HeLa cells, the K188R mutant failed to localize to cell membrane (Ambrosi_2013). Based on the highly conserved nature of the amino acid at position 563, despite limited clinical and functional data, this variant has been classified as a VUS - possibly pathogenic until additional evidence becomes available.

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