ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.416G>A (p.Ser139Asn) (rs76434661)

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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, Partners HealthCare 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 wit h hearing loss, at least 7 of whom were homozygous or compound heterozygous (Mar lin 2001, Azaiez 2004, Santos 2005, Rikkert 2005, Tang 2006, Dai 2009, Dodson 20 11, 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 ( , its frequency is low enough to be consistent with a recessive carrier frequenc y. In summary, this variant meets criteria to be classified as pathogenic for au tosomal 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 likely pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing The S139N variant in the GJB2 gene has been reported previously in association with autosomal recessive hearing loss when present with other pathogenic variants (Marlin et al., 2001; Snoeckx et al., 2005; Dodson et al., 2011). The S139N variant has also been 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). The variant is observed in 73/126324 (0.0578%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). S139N is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same residue (S139C) and in nearby residues (W134R, S138N, I140S, F142L, R143W/L/Q ) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. We consider S139N to be likely pathogenic.
Counsyl RCV000289146 SCV000487631 likely pathogenic Deafness, autosomal recessive 1A 2016-06-23 criteria provided, single submitter clinical testing
Counsyl RCV000409236 SCV000487632 likely pathogenic Deafness, autosomal dominant 3a 2016-06-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000289146 SCV000538032 likely pathogenic Deafness, autosomal recessive 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000289146 SCV000599750 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999925 SCV000603826 pathogenic not specified 2018-10-02 criteria provided, single submitter clinical testing The GJB2 c.416G>A; p.Ser139Asn variant (rs76434661) is reported in the literature in multiple unrelated individuals with sensorineural hearing loss, and in some of these cases a second pathogenic variant was identified (Dodson 2011, Gao 2016, Li 2014, Marlin 2001, Santos 2005). Additionally, this variant is reported to co-segregate with disease in a proband and an affected sibling (Santos 2005), and functional analysis shows the variant protein mislocalizes (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% (87/276710 alleles) in the Genome Aggregation Database. The serine at codon 139 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant may be tolerated. Based on available information, 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. 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.
Fulgent Genetics,Fulgent Genetics RCV000515309 SCV000611271 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; 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 RCV000289146 SCV000698255 pathogenic Deafness, autosomal recessive 1A 2017-08-28 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.416G>A (p.Ser139Asn) variant involves the alteration of a conserved nucleotide and is located in helical transmembrane region of the protein (UniProt). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index), however in silico predictions are not definitive. This variant was found in 37/121500 control chromosomes from ExAC and publications at an allele frequency of 0.0003045, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been detected in several non-syndromic hearing loss patients in compound heterozygous state with other pathogenic or potentially pathogenic variants (Marlin_2001, Santos_2005, Snoeckx_2005, Dodson_2011, Burke_2016). 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). Functional studies in HeLa cells showed defective localization and coupling (Fleishman_2006). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255015 SCV000700350 likely pathogenic not provided 2015-10-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000289146 SCV000914612 pathogenic Deafness, autosomal recessive 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 likely pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 139 of the GJB2 protein (p.Ser139Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs76434661, ExAC 0.05%). This variant has been observed as homozygous or in combination with another GJB2 variant in several individuals and families affected with hearing loss (PMID: 11493200, 21465647, 17041943, 16380907, 12172394, 27785406). ClinVar contains an entry for this variant (Variation ID: 44749). Experimental studies have shown that this missense change affects cellular localization in vitro (PMID: 16864573). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b 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

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