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

dbSNP: rs111033196

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000587104	SCV000227300	uncertain significance	not provided	2016-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Mass General Brigham 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	Autosomal recessive nonsyndromic hearing loss 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
Invitae	RCV000587104	SCV003298406	uncertain significance	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 127 of the GJB2 protein (p.Arg127Leu). This variant is present in population databases (rs111033196, gnomAD 0.2%). This missense change has been observed in individual(s) with bilateral hearing loss and/or deafness (PMID: 26346709, 29773520; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195204). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. Experimental studies have shown that this missense change affects GJB2 function (PMID: 26749107). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000587104	SCV003816810	uncertain significance	not provided	2020-10-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000666278	SCV001463371	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
GeneDx	RCV000587104	SCV002015572	likely pathogenic	not provided	2023-07-07	flagged submission	clinical testing	Identified in a cohort of nonsyndromic hearing loss patients in Guatemala and Brazil in published literature (Carranza et al., 2015; Felix et al., 2019); Published functional studies suggest a damaging effect (Kim et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 25388846, 17041943, 26540915, 27466889, 32596493, 29773520, 34652575, 34599368, 26346709, 26749107, 37106706)