Submissions for variant NM_004004.6(GJB2):c.617A>G (p.Asn206Ser)

gnomAD frequency: 0.00016  dbSNP: rs111033294

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211783	SCV000061530	pathogenic	Rare genetic deafness	2017-08-10	criteria provided, single submitter	clinical testing	The p.Asn206Ser variant in GJB2 has been reported in many individuals with heari ng loss (Kenna 2001, Wu 2002, Pandya 2003, Cryns 2004, Roux 2004, Snoeckx 2005, Marlin 2005, Putcha 2007, Rodriguez-Paris 2008, LMM data). At least 5 of these i ndividuals were homozygous or compound heterozygous with a second pathogenic var iant, and the variant segregated with hearing loss in at least 1 affected siblin g. This variant has also been identified in 0.05% (17/34414) of Latino chromosom es and 0.01% (9/126442) of European chromosomes by gnomAD (http://gnomad.broadin stitute.org); however, its frequency is low enough to be consistent with a reces sive carrier frequency. Computational prediction tools and conservation analysis are consistent with pathogenicity. Furthermore, in vitro functional studies sup port an impact on protein function (Mese 2004, Fleishman 2006, Mese 2008). In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss. ACMG/AMP Criteria applied: PM 3_VeryStrong, PM2_Supporting, PP3, PS3_Supporting, PP1.
Genetic Services Laboratory, University of Chicago	RCV000146025	SCV000193179	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724546	SCV000227301	pathogenic	not provided	2015-01-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724546	SCV000603822	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	The GJB2 c.617A>G; p.Asn206Ser variant (rs111033294) is reported in the literature in individuals with sensorineural hearing loss, either in the homozygous state (Marlin 2005) or in trans to other pathogenic GJB2 variants (Kenna 2001, Marlin 2001, Marlin 2005, Putcha 2007). This variant is found in the general population with an overall allele frequency of 0.01% (29/282456 alleles) in the Genome Aggregation Database and is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 44763). In functional assays, the p.Asn206Ser variant protein appears to be localized normally (Mese 2004, Fleishman 2006, Ambrosi 2013) and can form functional channels capable of electrical coupling, but these channels are less permeable to larger cations and exhibit reduced conductance compared to wildtype protein (Mese 2004, Mese 2008). Based on available information, this variant is considered to be pathogenic. References: Fleishman et al. The structural context of disease-causing mutations in gap junctions. J Biol Chem. 2006; 281(39): 28958-28963. Kenna et al. Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2001; 127(9): 1037-1042. Marlin et al. Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. Arch Otolaryngol Head Neck Surg. 2001; 127(8): 927-933. Marlin et al. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg. 2005; 131(6): 481-487. Mese et al. Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum Genet. 2004; 115(3): 191-199. Mese et al. Connexin26 deafness associated mutations show altered permeability to large cationic molecules. Am J Physiol Cell Physiol. 2008; 295(4): C966-974. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007; 9(7): 413-426.
Fulgent Genetics, Fulgent Genetics	RCV005003435	SCV000611273	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	2024-05-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037868	SCV000698269	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-03-10	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.617A>G (p.Asn206Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 10/119604 control chromosomes at a frequency of 0.0000836, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed the variant to result in channel malfunction with normal trafficking (Ambros_PNAS_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724546	SCV000957281	pathogenic	not provided	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 206 of the GJB2 protein (p.Asn206Ser). This variant is present in population databases (rs111033294, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 12172394, 14985372, 15070423, 15967879). 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: 44763). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 15241677, 18684989, 23967136). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004386	SCV001163358	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000037868	SCV001193901	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-01-03	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.617A>G(N206S) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID: 15070423, 14985372, 15967879, 12172394 and 11493200. Classification of NM_004004.5(GJB2):c.617A>G(N206S) 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.
INGEBI, INGEBI / CONICET	RCV001257566	SCV001434020	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 filtering allele frequency of c.617A>G, p.Asn206Ser is 0,031% in Latino chromosomes from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria meeting PM2_supp. This variant has been reported several times (more than 5) in trans with pathogenic variants individuals and also in homozygous state in hearing loss individuals (PMID: 23668481, 16380907, 17666888, 15967879, 12172394, 115556849, 15070423, 14985372, 11493200, 24158611; PM3_VeryStrong). p.Asn206Ser change in trans with a pathogenic variant segregated in one affected and unaffected siblings (Laboratory of Physiology and Genetics of Hearing, INGEBI internal data) meeting PP1_Moderate criteria. Computational data predicted a negative impact of the mutation to the protein (REVELscore: 0.775) applying to PP3 rule. Functional studies in Xenopus laevis oocytes and HeLa cells demonstrated a highly reduced function of mutant compared to WTCX26: decreased dye transfer, permeability to cationic and large molecules and conductance levels applying PS3_Moderate rule(PMID: 23967136, 18684989). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Sup, PP3, PP1_Mod , PM3_VeryStrong and PS3_Moderate.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000724546	SCV001468969	likely pathogenic	not provided		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000724546	SCV001476382	pathogenic	not provided	2021-02-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Experimental evidence regarding the effect of this variant on protein function is conflicting. Although studies show reduced channel permeability to large cationic molecules, they also show it is similar to wildtype (PMID: 18684989, 15241677, 16864573, 23967136). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
GeneDx	RCV000724546	SCV001982756	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Published in vitro studies demonstrate a damaging effect on the protein's function, with significantly reduced passage of dye and current through gap junction channels and slightly unstable hemichannels (Mese et al., 2008; Ambrosi et al., 2013); 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: 25262649, 26990548, 25087612, 15241677, 11493200, 25388846, 18988928, 17666888, 16864573, 15967879, 15070423, 14985372, 12865758, 12172394, 23891399, 23668481, 22796187, 24158611, 11556849, 16380907, 31370293, 31980526, 31160754, 34426522, 31589614, 33297549, 33096615, 36147510, 18684989, 23967136, 34032567)
Revvity Omics, Revvity	RCV000724546	SCV002024263	pathogenic	not provided	2019-05-11	criteria provided, single submitter	clinical testing
DASA	RCV000037868	SCV002061212	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-01-05	criteria provided, single submitter	clinical testing	The c.617A>G;p.(Asn206Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 44763; PMID: 23668481; 16380907; 17666888; 15967879; 12172394) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 18684989, 15241677, 16864573, 23967136) - PS3_moderate. The variant is present at low allele frequencies population databases (rs111033294– gnomAD 0.001840%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asn206Ser) was detected in trans with a pathogenic variant (PMID: 23668481; 16380907; 17666888; 15967879; 12172394) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
Natera, Inc.	RCV000037868	SCV001463360	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734554	SCV005361828	pathogenic	GJB2-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The GJB2 c.617A>G variant is predicted to result in the amino acid substitution p.Asn206Ser. This variant has been reported as pathogenic for autosomal recessive non-syndromic hearing loss (Marlin et al 2001. PubMed ID: 11493200; Wu et al. 2002. PubMed ID: 12172394; Roux et al. 2004. PubMed ID: 15070423; Snoeckx et al. 2005. PubMed ID: 16380907; Putcha et al. 2007. PubMed ID: 17666888). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.