Submissions for variant NM_004004.6(GJB2):c.133G>A (p.Gly45Arg)

gnomAD frequency: 0.00001  dbSNP: rs1326514987

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672597	SCV000797712	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2018-02-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825343	SCV000966638	uncertain significance	not specified	2018-07-25	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly45Arg variant in GJB2 has been reported in 1 individual with non-syndromic hearing los s (Rodriguez-Paris 2016). In addition, in vitro fluorescence microscopy studies suggest impaired permeability of IP3 through the connexin-26 (GJB2) channel for the p.Gly45Arg variant, potentially in an autosomal dominant manner (Rodriguez-P aris 2016). This variant has also been identified in 1/8722 of African chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org) . Computational prediction tools and conservation analysis suggest that the p.Gl y45Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Gly45Arg variant is unce rtain. ACMG/AMP Criteria applied: PM2; PP3; PS3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861812	SCV002306635	likely pathogenic	not provided	2021-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 45 of the GJB2 protein (p.Gly45Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with deafness (PMID: 27761313). ClinVar contains an entry for this variant (Variation ID: 556575). 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) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. Experimental studies have shown that this missense change affects GJB2 function (PMID: 27761313). This variant disrupts the p.Gly45 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15633193, 16885744, 18024254, 24785414). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001861812	SCV002522058	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	Reported heterozygous in a patient with post-lingual hearing loss in the published literature (PMID: 27761313); however, additional clinical and inheritance information was not provided; Published functional studies demonstrate that the Cx26 protein with this variant is able to formgap junction channels at cell membranes, but channels showreduced IP3 permeability when co-expressed withwildtype Cx26 channels, consistent witha dominant negative effect on channel function (PMID: 27761313); Located in the highly conserved parahelix region of connexin 26; Not observed at significant frequency in large population cohorts (gnomAD); 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: 36048236, 27761313, 37106706, 37892203)