ClinVar Miner

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

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Total submissions: 9
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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 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
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.

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