ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.380G>T (p.Arg127Leu) (rs111033196)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587104 SCV000227300 uncertain significance not provided 2016-12-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000175760 SCV000698254 uncertain significance not specified 2019-04-08 criteria provided, single submitter clinical testing Variant summary: GJB2 c.380G>T (p.Arg127Leu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain 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 0.00027 in 247720 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00027 vs 0.025), allowing no conclusion about variant significance. The variant, c.380G>T, has been reported in the literature without strong evidence for causality (Tang_2006, Cui_2015, Carranza_2015, , Gruber_2016, Felix_2019). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Non-Syndromic Hearing Loss. The variant displayed a defect in channel permeability in cell expressing homo-oligomeric GJ channels, but hetero-oligomeric GJ channels were no more than 50% or not significantly different from wt GJs, depending on the assay (Kim_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000175760 SCV000710879 uncertain significance not specified 2016-07-02 criteria provided, single submitter clinical testing The p.Arg127Leu variant in GJB2 has not been previously reported in individuals with hearing loss, but has been identified in 10/11538 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111 033196) and 3 control individuals (Tang 2008, Cui 2015). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Two other variants have been reported at the same amino acid position: the p.Arg127Cys variant of uncertain clinical significance and th e p.Arg127His which has been classified as benign. Computational prediction tool s and conservation analysis of the p.Arg127Leu variant do not provide strong sup port for or against an impact to the protein. In vitro studies suggest the varia nt may impact the protein (Yilmaz 2014, Kim 2016); however, these studies may no t accurately represent biological effects of the variant. In summary, the clinic al significance of the p.Arg127Leu variant is uncertain
Counsyl RCV000666278 SCV000790542 uncertain significance Deafness, autosomal recessive 1A 2017-03-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000587104 SCV000841708 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing

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