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

gnomAD frequency: 0.00047  dbSNP: rs76434661

Total submissions: 26

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	RCV000289146	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255015	SCV000965395	pathogenic	not provided	2024-11-30	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 autosomal recessive deafness (PMID: 11493200, 12172394, 16380907, 17041943, 21465647, 27785406). ClinVar contains an entry for this variant (Variation ID: 44749). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. 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	RCV000255015	SCV001143668	pathogenic	not provided	2021-07-13	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. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies in HeLa cells showed defective localization and coupling (PMID: 16864573). 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.
Baylor Genetics	RCV001004388	SCV001163360	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, 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
Revvity Omics, Revvity	RCV000255015	SCV002024257	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000289146	SCV003835740	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-03-07	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000289146	SCV005399501	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 89 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in an annotated transmembrane repeat (PMID: 16864573). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple compound heterozygote and homozygote individuals with deafness (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfection of mutant allele to HELA cells has shown mislocalisation (PMID: 16864573). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005007958	SCV005634663	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	2024-05-14	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
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