ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.416G>A (p.Ser139Asn)

gnomAD frequency: 0.00047  dbSNP: rs76434661
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Total submissions: 25
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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 RCV000037851 SCV000061513 pathogenic Rare genetic deafness 2019-01-31 criteria provided, single submitter clinical testing The p.Ser139Asn variant in GJB2 has been reported in at least 10 individuals with hearing loss, at least 7 of whom were homozygous or compound heterozygous (Marlin 2001, Azaiez 2004, Santos 2005, Rikkert 2005, Tang 2006, Dai 2009, Dodson 2011, Li 2014, Bonyadi 2014, Xing 2016, Plevova 2018). Additionally, this variant segregated with disease in one affected relative from one family (Santos 2005). In vitro functional studies support that the p.Ser139Asn variant impacts protein function (Fleishman 2006). Although this variant has been identified in 0.058% (75/128800) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PP1, PP3, PM2_Supporting, PS3_Supporting.
Genetic Services Laboratory,University of Chicago RCV000146022 SCV000193174 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000255015 SCV000321728 pathogenic not provided 2021-07-21 criteria provided, single submitter clinical testing Also identified in individuals with nonsyndromic hearing loss in whom no second pathogenic variant was identified (Wu et al., 2003; Azaiez et al., 2004; Bonyadi et al., 2014); Published functional studies suggest that the S139N variant is associated with abnormal localization of the protein (Fleishman et al., 2006); 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: 19235794, 20668687, 20083784, 26284228, 12172394, 17666888, 19173109, 20981092, 21162657, 27785406, 27535533, 30275481, 31160754, 16864573, 32003480, 32596493, 20234132, 28483220, 30344259, 26778469, 15365987, 15656949, 16380907, 19366456, 17041943, 26444186, 25266519, 12925341, 16950989, 21465647, 22695344, 24529908, 28576516, 27018795, 29754767, 23891399, 25388846, 27153395, 27792752, 11493200, 22995991, 25087612, 12910486, 24033266)
Counsyl RCV000409236 SCV000487632 likely pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2016-06-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000289146 SCV000538032 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2016-01-27 criteria provided, single submitter clinical testing The c.416G>A (p.Ser139Asn) missense variant in the GJB2 gene has been previously reported in at least nine individuals with autosomal recessive Nonsyndromic hearing loss and deafness. This c.416G>A variant has been observed in trans with the well-known 35delG variant in an affected individual (Marlin et al., 2001). An in vitro functional study showed this variant affects localization of the protein (Fleishman et al., 2006). The c.229C>T variant has been reported at low frequency in the c population databases (Exome Sequencing Project [ESP] = 0.0.081%, 1000 Genomes = 0.2%, and ExAC = 0.051%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.47; CADD = 24.9; PROVEAN = -2.62), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.416G>A (p.Ser139Asn) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss and deafness.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000289146 SCV000599750 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255015 SCV000603826 pathogenic not provided 2021-02-10 criteria provided, single submitter clinical testing The GJB2 c.416G>A; p.Ser139Asn variant (rs76434661) is reported in the literature in multiple unrelated individuals affected with sensorineural hearing loss, and in many individuals a second pathogenic variant was also identified (Dodson 2011, Gao 2016, Li 2014, Marlin 2001, Plevova 2018, Santos 2005, Snoeckx 2005, Tang 2006, Xing 2016). Additionally, the p.Ser139Asn variant is reported to co-segregate with disease in a proband and an affected sibling (Santos 2005), and functional analysis shows the variant protein fails to correctly localize to plasma membrane junctions (Fleishman 2006). This variant is classified as likely pathogenic or pathogenic by multiple laboratories in ClinVar (Variation ID: 44749). It is found in the general population with an overall allele frequency of 0.03% (89/282358 alleles) in the Genome Aggregation Database. The serine at codon 139 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.633). Based on available information, including its occurrence in multiple affected individuals, this variant is considered to be pathogenic. References: Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Fleishman SJ et al. The structural context of disease-causing mutations in gap junctions. J Biol Chem. 2006 Sep 29;281(39):28958-63. Gao Z et al. Application of SNPscan in Genetic Screening for Common Hearing Loss Genes. PLoS One. 2016 Oct 28;11(10):e0165650. Li Q et al. Comparative study of mutation spectrums of MT-RNR1 m.1555A>G, GJB2, and SLC26A4 between familial and sporadic patients with nonsyndromic sensorineural hearing loss in Chinese Han. Chin Med J (Engl). 2014;127(18):3233-7. Marlin S et al. Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. Arch Otolaryngol Head Neck Surg. 2001 Aug;127(8):927-33. Plevova P et al. Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia. Medicina (Kaunas). 2018 May 4;54(2):28. Santos RL et al. Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations. Int J Pediatr Otorhinolaryngol. 2005 Feb;69(2):165-74. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. Xing J et al. Genetic and clinical analysis of nonsyndromic hearing impairment in pediatric and adult cases. Balkan J Med Genet. 2016 Aug 2;19(1):35-42.
Fulgent Genetics,Fulgent Genetics RCV000515309 SCV000611271 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 RCV001844020 SCV000698255 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2022-02-18 criteria provided, single submitter clinical testing Variant summary: GJB2 c.416G>A (p.Ser139Asn) results in a conservative amino acid change located in the Connexin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251378 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00029 vs 0.025), allowing no conclusion about variant significance. The variant, c.416G>A, has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in compound heterozygous state with other pathogenic or potentially pathogenic variants (Marlin_2001, Santos_2005, Snoeckx_2005, Dodson_2011, Burke_2016, Plevova_2018). Additionally, it was found to segregate with disease in two affected siblings in a family (Santos_2005). This variant has also been found in hearing loss patients whose second mutation was not identified (Wu_2002, Azaiez_2004, Dai_2009, Bazazzadegan_2012, Bonyadi_2014). These data indicate that the variant is very likely to be associated with disease. Functional studies in HeLa cells showed defective localization and coupling (Fleishman_2006). 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, thirteen have classified as likely pathogenic/pathogenic while one has classified as benign. Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins NTD LLC (GA) RCV000255015 SCV000700350 likely pathogenic not provided 2015-10-12 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000289146 SCV000914612 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2018-10-22 criteria provided, single submitter clinical testing Across a selection of the available literature, the c.416G>A (p.Ser139Asn) missense variant has been identified in 13 individuals affected with hearing loss including eight compound heterozygotes (including two siblings), at least five of whom carried another known pathogenic variant in trans and at least six heterozygotes (Marlin et al. 2001; Azaiez et al. 2004; Santos et al. 2005; Snoeckx et al. 2005; Tang et al. 2006; Dai et al. 2009; Dodson et al. 2011; Bonyadi et al. 2014). The p.Ser139Asn variant was absent from 761 controls and is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Functional studies in HeLa cells transfected with the variant protein showed the p.Ser139Asn variant leads to mislocalization of the protein compared to wild type (Fleishman et al. 2006). Based on the collective evidence, the p.Ser139Asn variant is classified as pathogenic for autosomal recessive non-syndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000255015 SCV000965395 pathogenic not provided 2021-12-15 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 139 of the GJB2 protein (p.Ser139Asn). This variant is present in population databases (rs76434661, gnomAD 0.06%). This missense change has been observed in individuals with hearing loss (PMID: 11493200, 12172394, 16380907, 17041943, 21465647, 27785406). ClinVar contains an entry for this variant (Variation ID: 44749). 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: 16864573). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000255015 SCV001143668 pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.
Baylor Genetics RCV001004388 SCV001163360 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000289146 SCV001193789 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2019-12-17 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.416G>A(S139N) is classified as likely pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 11493200, 21465647, 25266519, 16950989, 22695344, 20234132, 17041943, 24529908, 12910486 and 12925341. Classification of NM_004004.5(GJB2):c.416G>A(S139N) is based on the following criteria: This variant 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.
CeGaT Center for Human Genetics Tuebingen RCV000255015 SCV001245649 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001109787 SCV001267157 benign Ichthyosis, hystrix-like, with hearing loss 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000255015 SCV001449023 pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678884 SCV000805077 pathogenic Hearing loss 2009-07-31 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255015 SCV001742430 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255015 SCV001951727 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000255015 SCV001972343 likely pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000255015 SCV002024257 pathogenic not provided 2020-02-13 no assertion criteria provided clinical testing
Center for Molecular Medicine, Children’s Hospital of Fudan University RCV000289146 SCV002073945 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2022-02-08 no assertion criteria provided clinical testing
Natera, Inc. RCV000289146 SCV002086048 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2020-02-12 no assertion criteria provided clinical testing

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