ClinVar Miner

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

gnomAD frequency: 0.00016  dbSNP: rs111033294
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Total submissions: 16
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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 RCV000515258 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; X-linked mixed hearing loss with perilymphatic gusher 2017-05-18 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.
Invitae RCV000724546 SCV000957281 pathogenic not provided 2021-12-12 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 non-syndromic hearing loss (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). 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: 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 Women's Health, 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 Inc 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 2022-05-19 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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, 18684989, 23967136)
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
PerkinElmer Genomics RCV000724546 SCV002024263 pathogenic not provided 2019-05-11 no assertion criteria provided clinical testing

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