Submissions for variant NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)

gnomAD frequency: 0.00011  dbSNP: rs104894397

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211765	SCV000061487	pathogenic	Rare genetic deafness	2010-09-27	criteria provided, single submitter	clinical testing	The Trp77Arg variant has been reported in many individuals with hearing loss and was absent from many controls (Carrasquillo 1997, Dalamon 2005, Marlin 2005, Pr asad 2000, Rabionet 2000, Shahin 2002, Snoeckx 2005). It was also found to segre gate with hearing loss in one large kindred (Carrasquillo 1997). In summary, thi s variant meets our criteria to be classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000080368	SCV000227324	pathogenic	not provided	2016-03-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000080368	SCV000322428	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the W77R variant did not form homotypic junctional channels, had impaired intercellular coupling, was inefficiently targeted to the plasma membrane, and was retained in intracellular stores (Martin et al., 1999; Bruzzone et al., 2003); 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: 12064630, 22975760, 14985372, 12505163, 10556284, 9328482, 25388846, 30139988, 15967879, 15964725, 10982180, 11102979, 16380907, 11935342, 22785241, 21726435, 31163360, 31827275, 32747562, 33096615, 31589614, 33105617)
Counsyl	RCV000412297	SCV000487394	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018526	SCV000917453	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-11-21	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.229T>C (p.Trp77Arg) results in a non-conservative amino acid change located in the connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 246400 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.1e-05 vs 0.025), allowing no conclusion about variant significance. c.229T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (Alvarez 2005, Carrasquillo 1997, Snoeckx 2005), and the variant was also found to segregate with the disease in one of these reported families (Carrasquillo 1997). These data indicate that the variant is very likely to be associated with disease. Functional studies have shown to have >99% reduction in junctional conductance in comparison to wild-type (Bruzzone_2003). Three 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000080368	SCV000958603	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 77 of the GJB2 protein (p.Trp77Arg). This variant is present in population databases (rs104894397, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 16467727, 16545002, 19371219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17003). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 10556284, 12064630, 12505163). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004394	SCV001163366	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018526	SCV001194211	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-09	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.229T>C(W77R) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 15967879, 22785241, 16380907, 10556284 and 12505163. Classification of NM_004004.5(GJB2):c.229T>C(W77R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018526	SCV001244781	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-08-30	criteria provided, single submitter	clinical testing	A homozygous missense variant was identified, NM_004004.5(GJB2):c.229T>C in exon 2 of the GJB2 gene. This substitution is predicted to create a major change from a tryptophan to an arginine at position 77, NP_003995.2(GJB2):p.(Trp77Arg). The tryptophan at this position has very high conservation (100 vertebrates, UCSC). In silico software predicts this variant to be disease causing. It is situated in the second transmembrane domain and functional studies have shown that it causes loss of channel activity. (Martin, PE. et al. (1999), Bruzzone, R. et al. (2002)). This variant is present in the gnomAD population database at a frequency of 0.0041% (10 in 246208, 0 homozygotes). It is one of the more frequent GJB2 variants and has been previously reported in patients with autosomal recessive deafness (Cryns, K. et al. (2004), Snoeckx, RL. et al. (2005), ClinVar). Based on current information, this variant has been classified as PATHOGENIC.
INGEBI, INGEBI / CONICET	RCV001257039	SCV001433544	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.229T>C, p.Trp77Arg variant has a filtering allele frequency of 0,00949% (7/34590 of Latino alleles with 95% CI) from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_supporting criteria. This variant has been identified in trans with different pathogenic variants in at least four patients: (PMID: 9328482, 11935342, 15964725, 16088916, 16380907, 22785241, PMID:16467727, 16545002, 19371219) applying to PM3_VeryStrong. Computational evidence showed a damage impact of the mutation to the protein (REVEL: 0.934) meeting PP3 rule. Functional studies in HeLa cells and Xenopus laevis oocytes demonstrated a deleterious effect of the mutant without dominant effect to Human CX26 by dye transfer and junctional conductance measurements assays. In both cases the levels of dye transfer and conductance did not exceed background levels (PMID: 10556284, PMID: 12064630, PMID: 12505163) applying to PS3_Moderate rule. Therefore, the c.229T>C variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2_Supporting, PM3_VeryStrong, PP3 and PS3_Moderate).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526518	SCV001736940	pathogenic	Hearing impairment		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000080368	SCV002024250	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV000018526	SCV002059939	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-08-01	criteria provided, single submitter	research	GJB2 c.229T>C, p.W77R alters a residue that is completely conserved in all sequenced vertebrates. The variant was previously reported to be deficient in formation of junctional channels (PMID: 18941476). The variant is homozygous in a Palestinian child with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is not present in 1300 Palestinian controls and is present in 10/251404 alleles on gnomAD, all heterozygotes.
Fulgent Genetics, Fulgent Genetics	RCV002496399	SCV002785873	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2022-05-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904848	SCV004726650	pathogenic	GJB2-related condition	2024-02-19	criteria provided, single submitter	clinical testing	The GJB2 c.229T>C variant is predicted to result in the amino acid substitution p.Trp77Arg. This variant has previously been reported in both homozygous and compound heterozygous individuals with sensorineural hearing loss and is causative for disease (Carrasquillo et al 1997. PubMed ID: 9328482; Raymond M et al 2019. PubMed ID: 31163360; Downie L et al 2019. PubMed ID: 31827275). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763492-A-G). This variant is interpreted as pathogenic.
OMIM	RCV000018526	SCV000038808	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	1997-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000018526	SCV001453346	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000080368	SCV001959295	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000080368	SCV001973315	pathogenic	not provided		no assertion criteria provided	clinical testing