ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.617A>G (p.Asn206Ser) (rs111033294)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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; 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724546 SCV000227301 pathogenic not provided 2015-01-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999827 SCV000603822 pathogenic not specified 2018-10-15 criteria provided, single submitter clinical testing The p.Asn206Ser variant (rs111033294) has been identified in as a homozygote (Marlin 2005), and in trans with various other pathogenic GJB2 variants (Kenna 2001, Marlin 2001, Marlin 2005, Putcha 2007), in several individuals diagnosed with sensorineural hearing loss. Functionally, p.Asn206Ser variant protein appears to be trafficked normally to the plasma membrane in multiple cell types (Mese 2004, Fleishman 2006, Ambrosi 2013) and can form channels capable of electrical coupling and allowing for diffusion of small tracer molecules (Mese 2004 and Mese 2008). However, passage of larger cations such as ethidium bromide is significantly reduced comparted to wild type GJB2 protein (Mese 2008), and the variant protein forms weakly unstable hemichannels (Ambrosi 2013). While found at an allele frequency of 0.008% in population databases such the NHLBI GO Exome Sequencing Project (ESP; identified in 1 out of 13,006 chromosomes) and in the Exome Aggregation Consortium (ExAC) browser (identified in 10 out of 119,172 chromosomes), this is consistent with an autosomal recessive carrier frequency. Therefore, the p.Asn206Ser variant satisfies our criteria for classification as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515258 SCV000611273 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000037868 SCV000698269 pathogenic Deafness, autosomal recessive 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.
Invitae RCV000724546 SCV000957281 pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 206 of the GJB2 protein (p.Asn206Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs111033294, ExAC 0.01%). This variant has been reported with a second GJB2 variant or as homozygous in individuals affected with non-syndromic hearing loss (PMID: 12172394, 14985372, 15070423, 15967879). ClinVar contains an entry for this variant (Variation ID: 44763). Experimental studies have shown that this missense change results in gap junctions that have moderately decreased conductance levels and transport of cationic molecules (PMID: 15241677, 18684989, 23967136). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004386 SCV001163358 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000037868 SCV001193901 pathogenic Deafness, autosomal recessive 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 hearing loss and deafness 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 (; calculated by using inverse allele frequency at, 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 Inc RCV000724546 SCV001476382 pathogenic not provided 2020-01-28 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. 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. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Segregation with disease in affected individuals from multiple families.
Baylor Genetics RCV000037868 SCV001524672 pathogenic Deafness, autosomal recessive 1A 2019-01-30 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Natera, Inc. RCV000037868 SCV001463360 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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