ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.339T>G (p.Ser113Arg) (rs80338946)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV001004771 SCV001164251 uncertain significance Nonsyndromic hearing loss and deafness 2019-08-16 reviewed by expert panel curation The allele frequency of the c.339T>G (p.Ser113Arg) variant in the GJB2 gene is 0.02% (3/10064) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.55, which does not meet the threshold necessary to apply PP3 or BP4. An in vitro functional study performed in Xenopus oocytes showed that variant junctional conductance for p.Ser113Arg was similar to water (negative control), indicating a loss of function impact on protein function (PS3_Moderate; PMID:12505163). The p.Ser113Arg variant has been reported in at least 5 probands with hearing loss, and 2 individuals were compound heterozygous for a pathogenic variant without phase confirmation (PM3, PMID: 15365987, 11439000, 9529365, 16380907, 23826813). In summary, although there is some evidence for pathogenicity the clinical significance of this variant is currently uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PS3_Moderate, PM3, PM2_Supporting.
Illumina Clinical Services Laboratory,Illumina RCV000357520 SCV000383015 uncertain significance Mutilating keratoderma 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000404004 SCV000383016 uncertain significance Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000020568 SCV000383017 likely pathogenic Deafness, autosomal recessive 1A 2017-04-27 criteria provided, single submitter clinical testing The GJB2 c.339T>G (p.Ser113Arg) missense variant has been reported in at least three studies in which it is found a total of four patients with an autosomal recessive form of nonsyndromic hearing loss, including in two in a compound heterozygous state and two in a heterozygous state where the zygosity of the variant is unknown (Kelly et al. 1998; Azaiez et al. 2004; Wang et al. 2013). The p.Ser113Arg variant was absent from 96 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Functional studies in Xenopus oocytes demonstrated that the variant resulted in only background levels of junctional conductance and did not induce the formation of homotypic junctional channels (Bruzzone et al. 2003). Structural modelling experiments showed that the variant is located at a conserved site (Fan et al. 2012). Based on the available evidence the p.Ser113Arg variant is classified as likely pathogenic for an autosomal recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000363717 SCV000383018 uncertain significance Hystrix-like ichthyosis with deafness 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000269032 SCV000383019 uncertain significance Keratitis ichthyosis and deafness syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000020568 SCV000800725 uncertain significance Deafness, autosomal recessive 1A 2017-06-13 criteria provided, single submitter clinical testing
GeneReviews RCV000020568 SCV000041044 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.

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