ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.493C>T (p.Arg165Trp) (rs376898963)

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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 RCV000154346 SCV000204009 likely benign not specified 2014-12-06 criteria provided, single submitter clinical testing p.Arg165Trp in exon 2 of GJB2: This variant has been identified in 7 individuals with hearing loss (Rickard 2001, Putcha 2007, Santos 2005); however several of these individuals did not carry a second GJB2 variant. This variant is not expec ted to have clinical significance because it is has been identified in 0.4% (77/ 16,586) of South Asian chromosomes by the Exome Aggregation Consortium (http://e xac.broadinstitute.org/;dbSNP rs376898963).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724444 SCV000227304 uncertain significance not provided 2014-11-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000404295 SCV000382993 likely benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000299050 SCV000382994 likely benign Hystrix-like ichthyosis with deafness 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000353875 SCV000382995 likely benign Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000406175 SCV000382996 likely benign Keratitis-Ichthyosis-Deafness Syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000668216 SCV000792784 uncertain significance Deafness, autosomal recessive 1A 2017-07-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000154346 SCV000917457 likely benign not specified 2018-05-02 criteria provided, single submitter clinical testing Variant summary: GJB2 c.493C>T (p.Arg165Trp) results in a non-conservative amino acid change located in the cysteine-rich domain (IPR019570) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 121246 control chromosomes (ExAC), predominantly observed within the South Asian subpopulation at a frequency of 0.0046, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00066 vs 0.025), allowing no conclusion about variant significance. The variant, c.493C>T, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (NSHL) (Rickard 2001, Gurtler 2008, RamShankar 2003, Hamid 2009), however in none of these cases was a second allele identified. In addition, Santos_2005, reports two families in which affected individuals do not carry the variant of interest, showing lack of cosegregation. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating the constriction of the channel pore in an intercellular dye transfer experiment (Xiao 2011). This defect might prevent the transmission of biochemically active molecules between cells, however, its implication in the pathomechanism is currently not clarified, and therefore this result does not allow convincing conclusions about the variant effect. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as likely benign.

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